Hexamethyleneiminyl tachykinin receptor antagonists

ABSTRACT

This invention provides a novel series of non-peptidyl compounds which are useful in the treatment or prevention of a physiological disorder associated with an excess of tachykinins. This invention also provides methods for the treatment of such physiological disorders as well as pharmaceutical formulations which employ these novel compounds.

BACKGROUND OF THE INVENTION

Tachykinins are a family of peptides which share the common amidated carboxy terminal sequence,

Phe—Xaa—Gly—Leu—Met—NH₂

hereinafter referred to as SEQ ID NO:1. Substance P was the first peptide of this family to be isolated, although its purification and the determination of its primary sequence did not occur until the early 1970's. Substance P has the following amino acid sequence,

Arg—Pro—Lys—Pro—Gln—Gln—Phe—Phe—Gly—Leu—Met—NH₂

hereinafter referred to as SEQ ID NO:2.

Between 1983 and 1984 several groups reported the isolation of two novel mammalian tachykinins, now termed neurokinin A (also known as substance K, neuromedin L, and neurokinin α), and neurokinin B (also known as neuromedin K and neurokinin β). see J. E. Maggio, Peptides, 6 (Supplement 3):237-243 (1985) for a review of these discoveries. Neurokinin A has the following amino acid sequence,

His—Lys—Thr—Asp—Ser—Phe—Val—Gly—Leu—Met—NH₂

hereinafter referred to as SEQ ID NO:3. The structure of neurokinin B is the amino acid sequence,

Asp—Met—His—Asp—Phe—Phe—Val—Gly—Leu—Met—NH₂

hereinafter referred to as SEQ ID NO:4.

Tachykinins are widely distributed in both the central and peripheral nervous systems, are released from nerves, and exert a variety of biological actions, which, in most cases, depend upon activation of specific receptors expressed on the membrane of target cells. Tachykinins are also produced by a number of non-neural tissues.

The mammalian tachykinins substance P, neurokinin A, and neurokinin B act through three major receptor subtypes, denoted as NK-1, NK-2, and NK-3, respectively. These receptors are present in a variety of organs.

Substance P is believed inter alia to be involved in the neurotransmission of pain sensations, including the pain associated with migraine headaches and with arthritis. These peptides have also been implicated in gastrointestinal disorders and diseases of the gastrointestinal tract such as inflammatory bowel disease. Tachykinins have also been implicated as playing a role in numerous other maladies, as discussed infra.

In view of the wide number of clinical maladies associated with an excess of tachykinins, the development of tachykinin receptor antagonists will serve to control these clinical conditions. The earliest tachykinin receptor antagonists were peptide derivatives. These antagonists proved to be of limited pharmaceutical utility because of their metabolic instability.

In essence, this invention provides a class of potent non-peptide tachykinin receptor antagonists. By virtue of their non-peptide nature, the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of known peptide-based tachykinin receptor antagonists.

SUMMARY OF THE INVENTION

This invention encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I

wherein

m is 0, 1, 2, or 3;

n is 0 or 1;

o is 0, 1, or 2;

p is 0 or 1;

R is phenyl, 2- or 3-indolyl, 2- or 3-indolinyl, benzothienyl, benzofuranyl, or naphthyl;

which groups may be substituted with one or two halo, C₁-C₃ alkoxy, trifluoromethyl, C₁-C₄ alkyl, phenyl-C₁-C₃ alkoxy, or C₁-C₄ alkanoyl groups;

R¹ is trityl, phenyl, diphenylmethyl, phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, hexamethyleneiminyl, benzofuranyl, tetrahydropyridinyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C₁-C₄ alkyl)-, phenyl-(C₁-C₄ alkoxy)-, quinolinyl-(C₁-C₄ alkyl)-, isoquinolinyl-(C₁-C₄ alkyl)-, reduced quinolinyl-(C₁-C₄ alkyl)-, reduced isoquinolinyl-(C₁-C₄ alkyl)-, benzoyl-(C₁-C₃ alkyl)-, C₁-C₄ alkyl, or —NH—CH₂—R⁵;

any one of which R¹ groups may be substituted with halo, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino;

or any one of which R¹ groups may be substituted with phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, C₁-C₄ alkyl, piperidinyl, pyridinyl, pyrimidinyl, C₂-C₆ alkanoylamino, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl;

any one of which groups may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino;

or R¹ is amino, a leaving group, hydrogen, C₁-C₄ alkylamino, or di(C₁-C₄ alkyl)amino;

R⁵ is pyridyl, anilino-(C₁-C₃ alkyl)-, or anilinocarbonyl;

R² is hydrogen, C₁-C₄ alkyl, C₁-C₄ alkylsulfonyl, carboxy-(C₁-C₃ alkyl)-, C₁-C₃ alkoxycarbonyl-(C₁-C₃ alkyl)-, or —CO—R⁶;

R⁶ is hydrogen, C₁-C₄ alkyl, C₁-C₃ haloalkyl, phenyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or —(CH₂)_(q)—R⁷;

q is 0 to 3;

R⁷ is carboxy, C₁-C₄ alkoxycarbonyl, C₁-C₄ alkylcarbonyloxy, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, C₁-C₆ alkoxycarbonylamino, or

phenoxy, phenylthio, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, indolinyl, indolyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, reduced quinolinyl, reduced isoquinolinyl, phenyl-(C₁-C₄ alkyl)-, quinolinyl-(C₁-C₄ alkyl)-, isoquinolinyl-(C₁-C₄ alkyl)-, reduced quinolinyl-(C₁-C₄ alkyl)-, reduced isoquinolinyl-(C₁-C₄ alkyl)-, benzoyl-C₁-C₃ alkyl;

any one of which R⁷ groups may be substituted with halo, trifluoromethyl, C₁-C₄ alkoxy, C₁-C₄ alkyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino;

or any one of which R⁷ groups may be substituted with phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, piperidinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl;

any of which groups may be substituted with halo, trifluoromethyl, amino, C₁-C₄ alkoxy, C₁-C₄ alkyl, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino;

R⁸ is hydrogen or C₁-C₆ alkyl;

R³ is phenyl, phenyl-(C₁-C₆ alkyl)-, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, C₁-C₈ alkyl, naphthyl, C₂-C₈ alkenyl, or hydrogen;

any one of which groups except hydrogen may be substituted with one or two halo, C₁-C₃ alkoxy, C₁-C₃ alkylthio, nitro, trifluoromethyl, or C₁-C₃ alkyl groups; and

R⁴ is hydrogen or C₁-C₃ alkyl; with the proviso that if R¹ is hydrogen or halo, R³ is phenyl, phenyl-(C₁-C₆ alkyl)-, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, or naphthyl; with the proviso that if R¹ is hydrogen or halo, R³ is phenyl, phenyl-(C₁-C₆ alkyl)-, C₃-C₈ cycloalkyl, C₅-C₈ cycloalkenyl, or naphthyl; or a pharmaceutically acceptable salt thereof.

In another embodiment, this invention encompasses the novel compounds of Formula I and the pharmaceutically acceptable salts, solvates, and prodrugs thereof, as well as pharmaceutical formulations comprising, as an active ingredient, a compound of Formula I in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel processes for the synthesis of the compounds of Formula I.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

All temperatures stated herein are in degrees Celsius (° C.). All units of measurement employed herein are in weight units except for liquids which are in volume units.

As used herein, the term “C₁-C₆ alkyl” refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl. The term “C₁-C₆ alkyl” includes within its definition the term “C₁-C₄ alkyl”.

“Divalent(C₁-C₄)alkyl” represents a straight or branched divalent saturated aliphatic chain having from one to four carbon atoms. Typical divalent(C₁-C₄)alkyl groups include methylene, ethylene, propylene, 2-methylpropylene, butylene and the like.

“Halo” represents chloro, fluoro, bromo or iodo.

“Halo(C₁-C₄)alkyl” represents a straight or branched alkyl chain having from one to four carbon atoms with 1, 2 or 3 halogen atoms attached to it. Typical halo(C₁-C₄)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl and the like.

“Hydroxy(C₁-C₄)alkyl” represents a straight or branched alkyl chain having from one to four carbon atoms with hydroxy group attached to it. Typical hydroxy(C₁-C₄)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyisopropyl, 2-hydroxypropyl, 2-hydroxybutyl, 3-hydroxyisobutyl, hydroxy-t-butyl and the like.

“C₁-C₆ alkylthio” represents a straight or branched alkyl chain having from one to six carbon atoms attached to a sulfur atom. Typical C₁-C₆ alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like. The term “C₁-C₆ alkylthio” includes within its definition the term “C₁-C₄ alkylthio”.

The term “C₂-C₈ alkenyl” as used herein represents a straight or branched, monovalent, unsaturated aliphatic chain having from two to eight carbon atoms. Typical C₂-C₆ alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.

“C₅-C₈ cycloalkenyl” represents a hydrocarbon ring structure containing from five to eight carbon atoms and having at least one double bond within that ring, which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, carbamoyl, N—(C₁-C₄)alkylcarbamoyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino or —(CH₂)_(a)—R^(c) where a is 1, 2, 3 or 4 and R^(c) is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino or di(C₁-C₄)alkylamino.

“C₁-C₄ alkylamino” represents a straight or branched alkylamino chain having from one to four carbon atoms attached to an amino group. Typical C₁-C₄ alkyl-amino groups include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino and the like.

“Di(C₁-C₄ alkyl)amino” represents a straight or branched dialkylamino chain having two alkyl chains, each having independently from one to four carbon atoms attached to a common amino group. Typical di(C₁-C₄)alkylamino groups include dimethylamino, ethylmethylamino, methylisopropylamino, t-butylisopropylamino, di-t-butylamino and the like.

“Arylsulfonyl” represents an aryl moiety attached to a sulfonyl group. “Aryl” as used in this term represents a phenyl, naphthyl, heterocycle, or unsaturated heterocycle moiety which is optionally substituted with 1, 2 or 3 substituents independently selected from halo, halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, carbamoyl, N—(C₁-C₄)alkylcarbamoyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino or —(CH₂)_(a)—R^(b) where a is 1, 2, 3 or 4; and R^(b) is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino or di(C₁-C₄)alkylamino.

The term “heterocycle” represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure. The heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C₁-C₄)-alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, carbamoyl, N—(C₁-C₄)-alkylcarbamoyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino or —(CH₂)_(a)—R^(d) where a is 1, 2, 3 or 4; and Rd is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino or di (C₁-C₄) alkylamino.

The term “unsaturated heterocycle” represents an unsubstituted or substituted stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ring which has one or more double bonds and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quarternized and including a bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The unsaturated heterocyclic ring may be attached at any heteroatom or carbon atom which affords a stable structure. The unsaturated heterocycle is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, carbamoyl, N—(C₁-C₄) alkylcarbamoyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino or —(CH₂)_(a)—R^(e) where a is 1, 2, 3 or 4; and R^(e) is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino or di (C₁-C₄) alkylamino.

Examples of such heterocycles and unsaturated heterocycles include piperidinyl, piperazinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinylsulfone, oxadiazolyl, triazolyl, tetrahydroquinolinyl, tetrahydrisoquinolinyl, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1,2,3,4-isoquinolin-7-yl and the like.

“C₁-C₆ alkoxy” represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom. Typical C₁-C₆ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy and the like. The term “C₁-C₆ alkoxy” includes within its definition the term “C₁-C₄ alkoxy”.

“C₂-C₆ alkanoyl” represents a straight or branched alkyl chain having from one to five carbon atoms attached to a carbonyl moiety. Typical C₂-C₆ alkanoyl groups include ethanoyl, propanoyl, isopropanoyl, butanoyl, t-butanoyl, pentanoyl, hexanoyl, 3-methylpentanoyl and the like.

“C₁-C₄ alkoxycarbonyl” represents a straight or branched alkoxy chain having from one to four carbon atoms attached to a carbonyl moiety. Typical C₁-C₄ alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl and the like.

“C₃-C₈ cycloalkyl” represents a saturated hydrocarbon ring structure containing from three to eight carbon atoms which is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from halo, halo(C₁-C₄)alkyl, C₁-C₄ alkyl, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, carbamoyl, N—(C₁-C₄)alkylcarbamoyl, amino, C₁-C₄ alkylamino, di(C₁-C₄)alkylamino or —(CH₂)_(a)—R^(f) where a is 1, 2, 3 or 4 and R^(f) is hydroxy, C₁-C₄ alkoxy, carboxy, C₁-C₄ alkoxycarbonyl, amino, carbamoyl, C₁-C₄ alkylamino or di(C₁-C₄)alkylamino. Typical C₃-C₈ cycloalkyl groups include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, 3-methyl-cyclopentyl, 4-ethoxycyclohexyl, 4-carboxycycloheptyl, 2-chlorocyclohexyl, cyclobutyl, cyclooctyl, and the like.

The term “amino-protecting group” as used in the specification refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound. Examples of such amino-protecting groups include formyl, trityl, phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, t-butoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)-prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)-ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, fluorenylmethoxycarbonyl (“FMOC”), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl and the like; benzoylmethylsulfonyl group, 2-nitrophenylsulfenyl, diphenylphosphine oxide and like amino-protecting groups. The species of amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups. Preferred amino-protecting groups are trityl, t-butoxycarbonyl (t-BOC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, “Protective Groups in Organic Chemistry”, (J. G. W. McOmie, ed., 1973), at Chapter 2; and T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis” (1991), at Chapter 7.

The term “carboxy-protecting group” as used in the specification refers to substituents of the carboxy group commonly employed to block or protect the carboxy functionality while reacting other functional groups on the compound. Examples of such carboxy-protecting groups include methyl, p-nitrobenzyl, p-methylbenzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylene-dioxybenzyl, benzhydryl, 4,4′-dimethoxy-benzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, 2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl and like moieties. Preferred carboxy-protecting groups are allyl, benzyl and t-butyl. Further examples of these groups are found in E. Haslam, supra, at Chapter 5, and T. W. Greene, et al., supra, at Chapter 5.

The term “leaving group” as used herein refers to a group of atoms that is displaced from a carbon atom by the attack of a nucleophile in a nucleophilic substitution reaction. The term “leaving group” as used in this document encompasses, but is not limited to, activating groups.

The term “activating group” as used herein refers a leaving group which, when taken with the carbonyl (—C═O) group to which it is attached, is more likely to take part in an acylation reaction than would be the case if the group were not present, as in the free acid. Such activating groups are well-known to those skilled in the art and may be, for example, succinimidoxy, phthalimidoxy, benzotriazolyloxy, benzenesulfonyloxy, methanesulfonyloxy, toluenesulfonyloxy, azido, or —O—CO—(C₄-C₇ alkyl).

The compounds used in the method of the present invention have multiple asymmetric centers. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.

The terms “R” and “S” are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in “Nomenclature of Organic Compounds: Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages 103-120.

In addition to the (R)-(S) system, the older D-L system is also used in this document to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix “D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and “L”, that of the isomer in which it is on the left.

As noted supra, this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I. A compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.

The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulfonic acid.

Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred.

It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.

The especially preferred compounds used in the methods of this invention are those of Formula I wherein

a) R is substituted or unsubstituted 2- or 3-indolyl, phenyl, or naphthyl;

b) n is 1;

c) R¹ is phenyl, substituted phenyl, piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, pyrrolidinyl, pyridyl, benzoyl, or morpholinyl;

d) R² is —CO—R⁶, C₁-C₄ alkylsulfonyl, or C₁-C₃ alkoxycarbonyl-(C₁-C₃ alkyl)-;

e) R³ is phenyl, substituted phenyl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, naphthyl or substituted naphthyl; and

f) R⁸ is hydrogen or methyl.

A most preferred group of compounds used in the methods of this invention are those of Formula I wherein R is optionally substituted indolyl, R¹ is substituted piperidinyl or substituted piperazinyl, R⁸ is hydrogen, and R² is acetyl or methylsulfonyl. Another preferred group of compounds used in the methods of this invention are those of Formula I wherein R is naphthyl, R¹ is optionally substituted phenyl, substituted piperidinyl or substituted piperazinyl, R² is acetyl or methylsulfonyl, and R³ is phenyl or substituted phenyl.

The especially preferred compounds of this invention are those of Formula I wherein

a) R is substituted or unsubstituted 2- or 3-indolyl, phenyl, or naphthyl;

b) n is 1;

c) R¹ is trityl, phenyl, substituted phenyl, piperidinyl, substituted piperidinyl, piperazinyl, substituted piperazinyl, pyrrolidinyl, pyridyl, benzoyl, or morpholinyl;

d) R² is —CO—R⁶, C₁-C₄ alkylsulfonyl, or C₁-C₃ alkoxycarbonyl-(C₁-C₃ alkyl)-;

e) R³ is phenyl, substituted phenyl, C₃-C₈ cycloalkyl, substituted C₃-C₈ cycloalkyl, naphthyl or substituted naphthyl; and

f) R⁸ is hydrogen or methyl.

The compounds of the present invention can be prepared by a variety of procedures well known to those of ordinary skill in the art. The particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound, and the relative lability of the substituted moieties.

Examples of such protocols are depicted in Schemes I through IV. The coupling of the substituted amine to the compound of Formula II (Method A) can be performed by many means known in the art, the particular methods employed being dependent upon the particular compound of Formula II which is used as the starting material and the type of substituted amine used in the coupling reaction. These coupling reactions frequently employ commonly used coupling reagents such as 1,1-carbonyl diimidazole, dicyclohexylcarbodiimide, diethyl azodicarboxylate, 1-hydroxybenzotriazole, alkyl chloroformate and triethylamine, phenyldichlorophosphate, and chlorosulfonyl isocyanate. Examples of these methods are described infra. After deprotection of the amino group, the compounds of Formula III are obtained.

The compound of Formula III is then reduced, converting the amide into an amine (Method B). Amides can be reduced to amines using procedures well known in the art. These reductions can be performed using lithium aluminum hydride as well as by use of many other different aluminum-based hydrides. Alternatively, the amides can be reduced by catalytic hydrogenation, though high temperatures and pressures are usually required for this. Sodium borohydride in combination with other reagents may be used to reduce the amide. Borane complexes, such as a borane dimethylsulfide complex, are especially useful in this reduction reaction.

The next step in Scheme I (Method C) is the selective acylation of the primary amine using standard methods, as typified by Method C. Because of the higher steric demand of the secondary amine, the primary amine is readily available for selective substitution.

This acylation can be done using any of a large number of techniques regularly employed by those skilled in organic chemistry. One such reaction scheme is a substitution using an anhydride such as acetic anhydride. Another reaction scheme often employed to acylate a primary amine employs a carboxylic acid preferably with an activating agent as described for Method A, supra. An amino-de-alkoxylation type of reaction uses esters as a means of acylating the primary amine. Activated esters which are attenuated to provide enhanced selectivity are very efficient acylating agents.

wherein:

R″ is equal to —(CH₂)_(m)—R¹; and

R² is not hydrogen.

Primary amines can also be acylated using amides to perform what is essentially an exchange reaction. This reaction is usually carried out with the salt of the amine. Boron trifluoride, usually in the form of a boron trifluoride diethyl ether complex, is frequently added to this reaction to complex with the leaving ammonia.

The next procedure is one of substitution of the secondary amine (Method D). For most of the compounds of Formula I this substitution is one of alkylation, acylation, or sulfonation. This substitution is usually accomplished using well recognized means. Typically, alkylations can be achieved using alkyl halides and the like as well as the well-known reductive alkylation methods as seen in Method G, Scheme II, supra, employing aldehydes or ketones. Many of the acylating reaction protocols discussed supra efficiently acylate the secondary amine as well. Alkyl- and aryl-sulfonyl chlorides can be employed to sulfonate the secondary amine.

In many instances one of the later steps in the synthesis of the compounds of Formula I is the removal of an amino- or carboxy-protecting group. Such procedures, which vary, depending upon the type of protecting group employed as well as the relative lability of other moieties on the compound, are described in detail in many standard references works such as T. W. Greene, et al., Protective Groups in Organic Synthesis (1991).

Schemes II and III depict alternative protocols and strategies for the synthesis of the compounds of Formula I. Many of the individual reactions are similar to those described in Scheme I but the reactions of Schemes II and III are done in a different, but yet well known to those skilled in the art, series of steps.

wherein R²a coupled with the carbonyl group to which it is attached is equal to R².

In order to preferentially prepare one optical isomer over its enantiomer, the skilled practitioner can proceed by one of two routes. The practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers. A commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al., “Enantiomers, Racemates, and Resolutions”, (1991).

In addition to the schemes described above, the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I. Scheme IV, infra, depicts a typical such synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation, in this case in the “R” configuration. These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.

Many of the synthetic steps employed in Scheme IV are the same as used in other schemes, especially Scheme III.

The following depicts representative examples of reaction conditions employed in the preparation of the compounds of Formula I.

Method A Coupling of Carboxylic Acid and Primary Amine to Form Amide

Preparation of 2-t-butoxycarbonylamino-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)propanamide

To a solution of N-(t-butoxycarbonyl)tryptophan (46.4 g, 152.6 mmoles) in 500 ml of dioxane was added carbonyl diimidazole (25.4 g, 156 mmoles) in a portionwise manner. The resulting mixture was stirred for about 2.5 hours at room temperature and then stirred at 45° C. for 30 minutes. Next, 2-methoxybenzylamine (20.7 ml, 158.7 mmoles) was added and the reaction mixture was then stirred for 16 hours at room temperature.

The dioxane was removed under reduced pressure. The product was partitioned between ethyl acetate and water and was washed successively with 1 N hydrochloric acid, saturated sodium bicarbonate solution, water, and brine, followed by drying over sodium sulfate and removal of the solvent. Final crystallization from methanol yielded 52.2 g of homogeneous product as yellow crystals. Yield 80.8%. m.p. 157-160° C.

Deprotection of Primary Amine

Synthesis of 2-amino-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)propanamide

To a mixture of the 2-t-butoxycarbonylamino-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)propanamide prepared supra (25.1 g, 59.2 mmoles) and anisole (12 ml, 110.4 mmoles) at 0° C. was added dropwise an aqueous solution of trifluoroacetic acid (118 ml, 1.53 moles) in 50 ml of water. This mixture was stirred for one hour at 0° C., followed by stirring for about 2.5 hours at ambient temperature. The mixture was then refrigerated for about 16 hours.

The volatiles were removed under reduced pressure. The product was partitioned between ethyl acetate and saturated sodium bicarbonate solution and was then washed with water followed by brine and then dried over sodium sulfate. The solvents were removed in vacuo. Recrystallization from a 1:1 diethyl ether/cyclohexane solution yielded 18.0 g (94.2%) of homogeneous product as an off-white powder. m.p. 104-108° C.

Method B Reduction of Amide Carbonyl

Synthesis of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]propane

To a refluxing solution of 2-amino-3-(1H-indol-3-yl)-N-(2-methoxybenzyl)propanamide (9.81 g, 30.3 mmoles), prepared as described supra, in 100 ml of anhydrous tetrahydrofuran was added dropwise a 10 M borane-methyl sulfide complex (9.1 ml, 91.0 mmoles). The resulting mixture was refluxed for about 2 hours. The mixture was cooled to room temperature and the excess borane was quenched by the dropwise addition of 160 ml of methanol. The resulting mixture was refluxed for 15 minutes and the methanol was removed under reduced pressure.

The residue was dissolved in a saturated methanol solution of hydrochloric acid (250 ml) and the solution refluxed for about 1 hour. The methanol was removed in vacuo and the product was isolated the addition of 5 N sodium hydroxide followed by extraction with diethyl ether. The product was then dried over sodium sulfate. The solvents were removed in vacuo. Flash chromatography (silica gel, eluting with methanol:methylene chloride:ammonium hydroxide, 10:100:0.5) provided 7.1 g of a mixture of the title compound (75%) and the indoline derivative of the title product (25%) as an amber oil.

Method C Acylation of Primary Amine

Preparation of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 17]

A mixture of 2-((4-phenyl)piperazin-1-yl)acetic acid, sodium salt (1.64 g, 6.8 mmoles) and triethylamine hydrobromide (1.24 g, 6.8 mmoles) in 35 ml of anhydrous dimethylformamide was heated to 50° C. and remained at that temperature for about 35 minutes. The mixture was allowed to cool to room temperature. 1,1-Carbonyl diimidazole (1.05 g, 6.5 mmoles) and 10 ml of anhydrous dimethylformamide were added to the mixture. The resulting mixture was stirred for about 3 hours at room temperature.

A solution of the 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]propane (75%) and the indoline derivative (25%) prepared supra, dissolved in 10 ml of anhydrous dimethylformamide was added to the previous reaction mixture. The resulting mixture was stirred for about 16 hours at room temperature. The dimethylformamide was removed under reduced pressure.

The title product and its indoline derivative were partitioned between ethyl acetate and water and then washed with brine, and dried over sodium sulfate. The solvents were removed in vacuo. This process yielded 3.2 g of a mixture of the title compound and its indoline derivative as a yellow oil. These two compounds were then separated using high performance liquid chromatography using a reverse phase column followed by a silica gel column to give the title product (5.2% yield) as a yellow foam.

Method D Techniques of Acylation of Secondary Amine

Preparation of 1-[N-ethoxycarbonyl-N-(2-methoxybenzyl)amino]-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 28]

To a solution of the 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.43 g, 0.85 mmole) and triethylamine (130 μl, 0.93 mmole) in 5 ml of anhydrous tetrahydrofuran, was added dropwise ethylchloroformate (89 μl, 0.93 mmole). The resulting mixture was stirred for about 16 hours at room temperature. The tetrahydrofuran was removed under reduced pressure.

The acylated product was partitioned between ethyl acetate and 0.2 N sodium hydroxide, and was then washed with water and brine successively, then dried over sodium sulfate. Flash chromatography (silica gel, methanol:methylene chloride, 2.5:97.5) provided 390 mg of homogeneous title product as a white foam.

Preparation of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)-N-(methylaminocarbonyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 29]

To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.40 g, 0.78 mmole) in 10 ml of anhydrous tetrahydrofuran was added dropwise methyl isocyanate (140μl, 2.3 mmoles). The resulting mixture was then stirred for 16 hours at room temperature. The tetrahydrofuran was removed in vacuo. The title product was isolated by consecutive washes with ethyl acetate, water, and brine, and then dried over sodium sulfate. Flash chromatography using silica gel and a methanol/methylene chloride (5/95) eluant provided 396 mg of the homogeneous product as a yellow oil.

Alkylation of Secondary Amine

Preparation of 1-[N-ethyl-N-(2-methoxybenzyl)amino]-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 9]

To a room temperature solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.41 g, 0.80 mmole) in 5 ml of anhydrous N,N-dimethylformamide were added ethyl iodide (120 μl, 1.5 mmoles) and potassium carbonate (120 mg, 0.87 mmole). This mixture was then heated to 50° C. and maintained at that temperature for about 4 hours after which it was stirred at room temperature for about 16 hours. The N,N-dimethylformamide was then removed under reduced pressure. The product was partitioned between ethyl acetate and water, and then washed with brine, before drying over sodium sulfate. The solvents were removed in vacuo. Preparative thin layer chromatography provided 360 mg of the title product as a yellow foam.

Method E Reduction of the Carbonyl of an Amide

Preparation of 1,2-diamino-3-(1H-indol-3-yl)propane

Boron trifluoride etherate (12.3 ml, 0.1 mmole) was added to a tetrahydrofuran (24.4 ml) solution of tryptophan amide (20.3 g, 0.1 mole) at room temperature with stirring. At reflux with constant stirring, borane methylsulfide (32.25 ml, 0.34 mole) was added dropwise. The reaction was heated at reflux with stirring for five hours. A tetrahydrofuran:water mixture (26 ml, 1:1) was carefully added dropwise. A sodium hydroxide solution (160 ml, 5N) was added and the mixture heated at reflux with stirring for sixteen hours.

The layers of the cooled mixture were separated and the aqueous was extracted twice with 40 ml each of tetrahydrofuran. These combined tetrahydrofuran extracts were evaporated. Ethyl acetate (800 ml) was added and this solution was washed three times with 80 ml saturated sodium chloride solution. The ethyl acetate extract was dried over sodium sulfate, filtered and evaporated to yield 18.4 g (97%) of the title compound.

Protection of Primary Amine

Preparation of the 2-amino-1-t-butoxycarbonylamino-3-(1H-indol-3-yl)propane.

Di-t-butyldicarbonate (0.90 ml, 3.9 mmoles) in 10 ml of tetrahydrofuran was added dropwise at room temperature to the 1,2-diamino-3-(1H-indol-3-yl)propane (1.06 g, 5.6 mmoles) produced supra, which was dissolved in 28 ml of tetrahydrofuran. This dropwise addition occurred over a 5 hour period. The solvent was evaporated. Flash chromatography using ethanol/ammonium hydroxide/ethylacetate yielded 0.51 g (1.76 mmoles, 31%) of the desired carbamate.

Acylation of the Secondary Amine

Preparation of 1-t-butoxycarbonylamino-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 151]

A slurry of 2-((4-phenyl)piperazin-1-yl)acetic acid (2.47 g, 11.2 mmoles) and triethylamine (3.13 ml, 22.5 mmoles) in acetonitrile (1200 ml) was heated to reflux briefly with stirring. While the resulting solution was still warm carbonyldiimidazole (1.82 g, 11.2 mmoles) was added and the mixture was heated at reflux for 10 minutes. The 2-amino-1-t-butoxycarbonylamino-3-(1H-indol-3yl)-propane (3.25 g, 11.2 mmoles) in 50 ml of acetonitrile was then added to the reaction. The resulting mixture was refluxed with stirring for 30 minutes and was then stirred at room temperature overnight.

The reaction mixture was then refluxed with stirring for 5 hours and the solvent was then removed in vacuo. The resulting oil was washed with a sodium carbonate solution, followed by six washes with water, which was followed by a wash with a saturated sodium chloride solution. The resulting liquid was dried over sodium sulfate and filtered. The retained residue was then dried in vacuo. The filtrate was reduced in volume and then partially purified by chromatography. The sample from the chromatograaphy was pooled with the residue retained by the filter, combining for 3.94 grams (72% yield) of the title product.

Method F Deprotection of Primary Amine

Synthesis of 1-amino-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 150]

To an ice cold solution of 70% aqueous trifluoroacetic acid (2.8 ml of trifluoroacetic acid in 4.0 ml total volume) were added 1-t-butoxycarbonylamino-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.80 g, 1.63 mmoles) and anisole (0.4 ml). This mixture was stirred for 35 minutes, resulting in a clear solution. The solution was then stirred for an additional hour and then evaporated.

Ethyl acetate was then added to the resulting liquid, followed by a wash with a sodium carbonate solution. This wash was then followed by three washes with a saturated sodium chloride solution. The resulting solution was then dried over sodium sulfate, filtered and evaporated, resulting in 0.576 g (90% yield) of the title product.

Method G Reductive Alkylation of Primary Amine

Preparation of 1-[N-(2-chlorobenzyl)amino]-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane.

[Compound of Example 2]

2-Chlorobenzaldehyde (0.112 g, 0.8 mmole) was combined with the 1-amino-3-(1H-indol-3-yl)-2-[N-(2-((4-phenyl)piperazin-1-yl)acetyl)amino]propane (0.156 g, 0.398 mmole) in toluene. The resulting mixture was then stirred and warmed, and then evaporated. Toluene was then added to the residue and this mixture was again evaporated. Tetrahydrofuran was added to the residue and the mixture was then cooled in an ice bath.

Sodium cyanoborohydride (0.025 g, 0.4 mmole) was then added to the reaction mixture. Gaseous hydrogen chloride was periodically added above the liquid mixture. The mixture was stirred at room temperature for 16 hours and then reduced in volume in vacuo.

A dilute hydrochloric acid solution was then added to the residue and the solution was then extracted twice with ether. The acidic aqueous extract was basified by the dropwise addition of 5N sodium hydroxide. This basified solution was then extracted three times with ethyl acetate. The combined ethyl acetate washes were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. This process was followed by chromatography yielding 0.163 g (79% yield) of the title product.

Method H Tritylation

Preparation of 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanamide.

Tryptophan amide (26.43 g, 0.130 mole) was suspended in 260 ml of methylene chloride and this mixture was flushed with nitrogen and then put under argon. Trityl chloride (38.06 g, 0.136 mole) was dissolved in 75 ml of methylene chloride. The trityl chloride solution was slowly added to the tryptophan amide solution which sat in an ice bath, the addition taking about 25 minutes. The reaction mixture was then allowed to stir overnight.

The reaction mixture was then poured into a separation funnel and was washed with 250 ml of water, followed by 250 ml of brine. As the organic layer was filtering through sodium sulfate to dry, a solid precipitated. The filtrate was collected and the solvent was evaporated.

Ethyl acetate was then added to the pooled solid and this mixture was stirred and then refrigerated overnight. The next day the resulting solid was washed several times with cold ethyl acetate and then dried in vacuo. Yield 49.76 g (85.9%).

Reduction of Carbonyl

Preparation of 1-amino-3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propane

Under argon the 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanamide (48.46 g, 0.108 mole) was suspended in 270 ml of tetrahydrofuran. This mixture was then heated to reflux. Borane-methyl sulfide complex (41.3 g, 0.543 mole) was then slowly added to the reaction mixture. All of the starting amide dissolved during the addition of the borane-methyl sulfide complex. This solution was then stirred overnight in an 83° C. oil bath.

After cooling a 1:1 mixture of tetrahydrofuran:water (75 ml total) was then added to the solution. Sodium hydroxide (5N, 230 ml) was then added to the mixture, which was then heated to reflux for about 30 minutes.

After partitioning the aqueous and organic layers, the organic layer was collected. The aqueous layer was then extracted with tetrahydrofuran. The organic layers were combined and the solvents were then removed by evaporation. The resulting liquid was then partitioned between ethyl acetate and brine and was washed a second time with brine. The solution was then dried over sodium sulfate and the solvents were removed in vacuo to yield 48.68 grams of the desired intermediate.

Substitution of Primary Amine

Preparation of 1-[N-(2-methoxybenzyl)amino]-3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propane

To a mixture of 1-amino-3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propane (48.68 g, 0.109 mole) dissolved in toluene (1.13 l) was added 2-methoxybenzaldehyde (23.12 g, 0.169 mole), the 2-methoxybenzaldehyde having been previously purified by base wash. The reaction mixture was stirred overnight. The solvents were then removed in vacuo.

The recovered solid was dissolved in 376 ml of a 1:1 tetrahydrofuran:methanol mixture. To this solution was added sodium borohydride (6.83 g, 0.180 mole). This mixture was stirred on ice for about 4 hours. The solvents were removed by evaporation. The remaining liquid was partitioned between 1200 ml of ethyl acetate and 1000 ml of a 1:1 brine:20N sodium hydroxide solution. This was extracted twice with 500 ml of ethyl acetate each and then dried over sodium sulfate. The solvents were then removed by evaporation overnight, yielding 67.60 grams (>99% yield) of the desired product.

Method J Tritylation

Preparation of 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid [N-trityltryptophan]

Chlorotrimethylsilane (70.0 ml, 0.527 moles) was added at a moderate rate to a stirring slurry of tryptophan (100.0 g, 0.490 mole) in anhydrous methylene chloride (800 ml) under a nitrogen atmosphere. This mixture was continuously stirred for 4.25 hours. Triethylamine (147.0 ml, 1.055 moles) was added followed by the addition of a solution of triphenylmethyl chloride (147.0 g, 0.552 mole) in methylene chloride (400 ml) using an addition funnel. The mixture was stirred at room temperature, under a nitrogen atmosphere for at least 20 hours. The reaction was quenched by the addition of methanol (500 ml).

The solution was concentrated on a rotary evaporator to near dryness and the mixture was redissolved in methylene chloride and ethyl acetate. An aqueous work-up involving a 5% citric acid solution (2×) and brine (2×) was then performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The solid was dissolved in hot diethyl ether followed by the addition of hexanes to promote crystallization. By this process 173.6 g (0.389 mole) of analytically pure 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid was isolated as a light tan solid in two crops giving a total of 79% yield.

Coupling

Preparation of 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide

To a stirring solution of 3-(1H-indol-3-yl)-2-(N-triphenylmethylamino)propanoic acid (179.8 g, 0.403 mole), 2-methoxybenzylamine (56.0 ml, 0.429 mole), and hydroxybenzotriazole hydrate (57.97 g, 0.429 mole) in anhydrous tetrahydrofuran (1.7 L) and anhydrous N,N-dimethylformamide (500 ml) under a nitrogen atmosphere at 0° C., were added triethylamine (60.0 ml, 0.430 mole) and 1-(3-dimethylaminopropyl)-3-ethoxycarbodiimide hydrochloride (82.25 g, 0.429 mole). The mixture was allowed to warm to room temperature under a nitrogen atmosphere for at least 20 hours. The mixture was concentrated on a rotary evaporator and then redissolved in methylene chloride and an aqueous work-up of 5% citric acid solution (2×), saturated sodium bicarbonate solution (2×), and brine (2×) was performed. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness on a rotary evaporator. The title product was then filtered as a pink solid in two lots. Isolated 215.8 g (0.381 mole) of analytically pure material (95% yield).

Reduction

Preparation of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane

Red-Al®, [a 3.4 M, solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene] (535 ml, 1.819 moles), dissolved in anhydrous tetrahydrofuran (400 ml) was slowly added using an addition funnel to a refluxing solution of the acylation product, 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (228.6 g, 0.404 mols) produced supra, in anhydrous tetrahydrofuran (1.0 liter) under a nitrogen atmosphere. The reaction mixture became a purple solution. The reaction was quenched after at least 20 hours by the slow addition of excess saturated Rochelle salt solution (potassium sodium tartrate tetrahydrate). The organic layer was isolated, washed with brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil on a rotary evaporator. No further purification was done and the product was used directly in the next step.

Method K Acylation

Preparation of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)-acetylamino]-2-(N-triphenylmethylamino)propane

To a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)amino]-2-(N-triphenylmethylamino)propane (0.404 mole) in anhydrous tetrahydrofuran (1.2 liters) under a nitrogen atmosphere at 0° C. was added triethylamine (66.5 ml, 0.477 mole) and acetic anhydride (45.0 ml, 0.477 mole). After 4 hours, the mixture was concentrated on a rotary evaporator, redissolved in methylene chloride and ethyl acetate, washed with water (2×) and brine (2×), dried over anhydrous sodium sulfate, filtered, and concentrated to a solid on a rotary evaporator. The resulting solid was dissolved in chloroform and loaded onto silica gel 60 (230-400 mesh) and eluted with a 1:1 mixture of ethyl acetate and hexanes. The product was then crystallized from an ethyl acetate/hexanes mixture. The resulting product of 3-(1H-indol-3-yl)-1-(N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane was crystallized and isolated over three crops giving 208.97 grams (87% yield) of analytically pure material.

Method L Detritylation

Preparation of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane

Formic acid (9.0 ml, 238.540 mmoles) was added to a stirring solution of 3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]-2-(N-triphenylmethylamino)propane (14.11 g, 23.763 mmoles) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0 N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.

Method M Bromoacetylation

Preparation of 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane

To a stirring solution of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. was added diisopropylethylamine (4.1 ml, 23.537 mmoles) and bromoacetyl bromide (2.05 ml, 23.530 mmoles). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.

Method N Nucleophilic Displacement

Preparation of 1-[N-(2-methoxybenzyl)acetylamino]-3- (1H-indol-3-yl)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)amino]propane

[Compound of Example 74]

1-Cyclohexylpiperazine (3.65 g, 22.492 mmoles) was added to a stirring solution of 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (21.369 mmoles) and powdered potassium carbonate (3.56 g, 25.758 mmols) in methylene chloride under a nitrogen atmosphere. The reaction mixture was stirred overnight at room temperature. The salts were filtered and the solution concentrated to a brown foam on a rotary evaporator. The desired product was purified on a Prep 500 column using a 10 L gradient starting with 100% methylene chloride and ending with 5% methanol/94.5% methylene chloride/0.5% ammonium hydroxide. Impure fractions were combined and purified further by reverse phase preparative high performance liquid chromatography (methanol/acetonitrile/water/ammonium acetate). After combining the material from both chromatographic purifications the title compound (10.43 g, 18.663 mmoles) was isolated (87% yield).

An alternative means of acylation of the primary amine as shown in the final step of the synthesis protocol of Scheme IV is by means of reacting a compound of the formula

with a potassium carboxylate of the formula

in the presence of isobutylchloroformate and N-methylmorpholine. This reaction is usually performed in the presence of a non-reactive solvent such as methylene chloride at cool temperatures, usually between −30° C. and 10° C., more preferably at temperatures between −20° C. and 0° C. In this reaction equimolar amounts of the two reactants are generally employed although other ratios are operable. An example of this preferred means of acylating the primary amine is shown in the following example.

Method P

Preparation of (R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-((4-cyclohexyl)piperazin-1-yl)acetyl)aminolpropane

[Compound of Example 75]

The title compound was prepared by first cooling 2-((4-cyclohexyl)piperazin-1-yl)acetic acid potassium salt to a temperature between −8° C. and −15° C. in 5 volumes of anhydrous methylene chloride. To this mixture was then added isobutylchloroformate at a rate such that the temperature did not exceed −8° C. This reaction mixture was then stirred for about 1 hour, the temperature being maintained between −8° C. and −15° C.

To this mixture was then added (R)-2-amino-3-(1H-indol-3-yl)-1-(N-(2-methoxybenzyl)acetylamino]propane dihydrochloride at such a rate that the temperature did not exceed 0° C. Next added to this mixture was N-methyl morpholine at a rate such that the temperature did not exceed 0° C. This mixture was then stirred for about 1 hour at a temperature between −15° C. and −8° C.

The reaction was quenched by the addition of 5 volumes of water. The organic layer was washed once with a saturated sodium bicarbonate solution. The organic phase was then dried over anhydrous potassium carbonate and filtered to remove the drying agent. To the filtrate was then added 2 equivalents of concentrated hydrochloric acid, followed by 1 volume of isopropyl alcohol. The methylene chloride was then exchanged with isopropyl alcohol under vacuum by distillation.

The final volume of isopropyl alcohol was then concentrated to three volumes by vacuum. The reaction mixture was cooled to 20° C. to 25° C. and the product was allowed to crystallize for at least one hour. The desired product was then recovered by filtration and washed with sufficient isopropyl alcohol to give a colorless filtrate. The crystal cake was then dried under vacuum at 50° C.

The following table illustrates many of the compounds produced using essentially the steps described in Schemes I through IV. A person of ordinary skill in the art would readily understand that a certain order of steps must be employed in many instances to avoid reactions other than the one sought. For example, as in the above methods, it is frequently necessary to employ a protecting group in order to block a reaction at a particular moiety.

The abbreviations used in the following table are commonly used in the field and would be readily understood by a practitioner in the field. For example, the abbreviation “Ph” refers to a phenyl group, “i-Pr” refers to an isopropyl group, “Me” describes a methyl group, “Et” refers to an ethyl group, “t-Bu” describes a tert-butyl group, and the like.

In the following table, the first column gives the example number of the compound. The next columns (may be one, two, or three columns) describe the substitution patterns of the particular example. The column entitled “Mp ° C.” gives the melting point of the compound if it is a solid or notes the form of the substance at ambient temperature. The next column, entitled “MS”, defines the mass of the compound as determined by mass spectroscopy. The following column gives the nuclear magnetic resonance profile of the example compound as synthesized. The final columns give the molecular formula of the example compound as well as its elemental analysis.

Analysis % Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 1 H H foam 481 (M⁺) CDCl₃ 2.28(m, 1H), 2.32- C₃₀H₃₅N₅O 74.81 7.32 14.54 2.45(m, 2H), 2.45-2.61(m, 74.83 7.38 14.67 2H), 2.73(m, 1H), 2.79-3.15 (m, 8H), 3.21(m, 1H), 3.96 (ABq, J=8Hz, Δν=20Hz, 2H), 4.50(m, 1H), 6.78-6.99 (m, 3H), 7.04(m, 1H), 7.10- 7.59(m, 11H), 7.66(d, J=8 Hz, 1H), 8.10(br s, 1H) 2 H 2-Cl foam 515, 517 DMSO-d₆ 2.33-2.50(m, 4H), (M⁺'s for 2.56-2.75(m, 2H), 2.75-3.09 Cl (m, 8H), 3.20(m, 1H), 4.78 isotopes) (s, 2H), 5.21(m, 1H), 6.78 (t, J=8Hz, 1H), 6.88(d, J=8 Hz, 2H), 6.98(t, J=8Hz, 1H), 7.06(t, J=8Hz, 1H), 7.13(m, 1H), 7.13-7.31(m, 4H), 7.34(d, J=7Hz, 1H), 7.39(dd, J=2, 6Hz, 1H), 7.50(dd, J=2, 7Hz, 1H), 7.55(d, J=8Hz, 1H), 7.61 (d, J=7Hz, 1H), 10.81(br s, 1H) 3 H 2-CF₃ foam 549 CDCl₃ 2.12(m, 1H), 2.36- C₃₁H₃₄F₃N₅O (M⁺) 2.44(m, 2H), 2.44-2.60(m, Exact 2H), 2.77-3.09(m, 10H), Mass FAB 4.02(s, 2H), 4.50(m, 1H), theory: 6.73-7.00(m, 3H), 7.00-7.56 550.2794 (m, 9H, 7.56-7.85(m, 3H), found: 8.16(br s, 1H) 550.2801 4 H 2-OMe foam 512 CDCl₃ 2.30-2.43(m, 2H), C₃₁H₃₇N₅O₂ 72.77 7.29 13.69 (RS) (M + 1⁺) 2.43-2.54(m, 2H), 2.70-3.10 72.49 7.33 13.90 (m, 11H), 3.82(s, 3H), 3.84 (m, 2H), 4.44(m, 1H), 6.74- 6.94(m, 6H), 7.04(m, 1H), 7.07-7.36(m, 7H), 7.64(d, J=8Hz, 1H), 8.09(br s, 1H) 5 H 2-OMe foam 512 CDCl₃ 2.30-2.43(m, 2H), C₃₁H₃₇N₅O₂ 72.77 7.29 13.69 (R) (M + 1⁺) 2.43-2.56(m, 2H), 2.64-3.12 72.58 7.39 13.65 (m, 11H), 3.59-3.93(m, 2H), 3.82(s, 3H), 4.43(m, 1H), 6.68-6.96(m, 6H), 7.03(m, 1H), 7.07-7.45(m, 7H), 7.66 (d, J=8Hz, 1H), 8.04(br s, 1H) 6 H 2-OMe foam 512 CDCl₃ 2.22-2.38(m, 2H), C₃₁H₃₇N₅O₂ 72.77 7.29 13.69 (S) (M + 1⁺) 2.38-2.50(m, 2H), 2.50-3.27 73.01 7.50 13.69 (m, 11H), 3.84(s, 3H), 3.96 (ABq, J=13Hz, Δν=21Hz, 2H), 4.27(m, 1H), 6.75-6.97 (m, 6H), 6.99-7.39(m, 8H), 7.63(d, J=8Hz, 1H), 8.12 (br s, 1H) 7 H 3-OMe foam 511 (M⁺) CDCl₃ 7:3 mixture of amide C₃₁H₃₇N₅O₂ 72.77 7.29 13.69 rotamers 2.20-3.74(m, 73.00 7.19 13.91 14H), 3.74(m, 1H), 3.76(s, 3/10•3H), 3.80(s, 7/10•3H), 4.13(ABq, J=14Hz, Δν=50 Hz, 7/10•2H), 4.67(m, 1H), 4.70(ABq, J=14Hz, Δν=160 Hz, 3/10•2H), 6.82-7.00(m, 6H), 7.00-7.45(m, 8H), 7.59 (d, J=8Hz, 1H), 8.10(br s, 3/10•1H), 8.41(br s, 7/10•1H) 8 H 4-OMe foam 511 (M⁺) CDCl₃ 2.21-2.63(m, 4H), C₃₁H₃₇N₅O₂ 72.77 7.29 13.69 2.63-2.90(m, 4H), 2.90-3.40 72.58 7.35 13.70 (m, 6H), 3.75(m, 1H), 3.77 (s, 3H), 4.04(ABq, J=12Hz, Δν=54Hz, 2H), 4.64(m, 1H), 6.83-6.95(m, 5H), 6.95- 7.48(m, 8H), 7.50-7.75(m, 2H), 8.23(br s, 1H) 9 Et 2-OMe foam 540 CDCl₃ 1.04(t, J=8Hz, 3H), C₃₃H₄₁N₅O₂ 73.44 7.66 12.98 (M + 1⁺) 2.32-2.43(m, 2H), 2.43-2.66 73.21 7.63 13.14 (m, 6H), 2.83-2.91(m, 4H), 2.94(d, J=5Hz, 2H), 3.08(t, J=6Hz, 2H), 3.65(ABq, J=14Hz, Δν=22Hz, 2H), 3.77(s, 3H), 4.41(q, J=6Hz, 1H), 6.78-6.96(m, 6H), 7.06- 7.29(m, 6H), 7.33(d, J=8 Hz, 1H), 7.40(d, J=7Hz, 1H), 7.64(d, J=8Hz, 1H), 7.99(br s, 1H) 10 MeO(OC)CH₂ 2-OMe foam 584 CDCl₃ 2.37-2.47(m, 2H), C₃₄H₄₁N₅O₄ 69.96 7.08 11.99 (M + 1⁺) 2.50-2.58(m, 2H), 2.78-2.98 69.69 6.98 11.87 (m, 6H), 3.00(s, 2H), 3.12(t, J=6Hz, 2H), 3.37(ABq, J=18Hz, Δν=26Hz, 2H), 3.65(s, 3H), 3.77(s, 3H), 3.83(s, 2H), 4.45(m, 1H), 6.80-6.92(m, 5H), 7.00(s, 1H), 7.10-7.40(m, 8H), 7.70 (d, J=9Hz, 1H), 8.08(s, 1H) 11 HO(OC)CH₂ 2-OMe 95-100 570 DMSO-d₆ 2.31-2.49(m, C₃₃H₃₉N₅O₄ 69.57 6.90 12.29 (M + 1⁺) 4H), 2.75(d, J=8Hz, 2H), 69.80 6.79 11.99 2.81-3.05(m, 7H), 3.13-3.49 (m, 3H), 3.65-3.80(m, 2H), 3.71(s, 3H), 4.20(m, 1H), 6.78(t, J=8Hz, 1H), 6.83- 6.98(m, 5H), 7.00-7.10(m, 2H), 7.21(t, J=8Hz, 3H), 7.30(t, J=9Hz, 2H), 7.56 (br d, J=8Hz, 2H), 10.81(br s, 1H) 12 MeCO H foam 523 (M⁺) DMSO-d₆ 1:1 mixture of C₃₂H₃₇N₅O₂ 73.39 7.12 13.37 amide rotamers 1.99(s, 73.67 7.23 13.60 1/2•3H), 2.07(s, 1/2•3H), 2.20-2.50(m, 4H), 2.69-2.95 (m, 4H), 2.95-3.12(m, 4H), 3.12-3.52(m, 1/2•1H+1H), 3.63(m, 1/2•1H), 4.40(m, 1H), 4.51(ABq, J=16Hz, Δν=140Hz, 1/2•2H), 4.54 (ABq, J=16Hz, Δν=30Hz, 1/2•2H), 6.78(t, J=8Hz, 1H), 6.86-6.94(m, 2H), 6.98 (m, 1H), 7.03-7.15(m, 4H), 7.15-7.38(m, 6H), 7.50-7.60 (m, 1.5H), 7.74(d, J=8Hz, 1/2•1H), 10.93(br s, 1H) 13 MeCO 2-Cl foam 557 (M⁺) DMSO-d₆ 3:2 mixture of C₃₂H₃₆ClN₅O₂ 68.86 6.50 12.55 amide rotamers 1.93(s, 69.06 6.48 12.56 2/5•3H), 2.09(s, 3/5•3H), 2.25-2.50(m, 4H), 2.70-2.96 (m, 4H), 2.96-3.19(m, 4H), 3.20-3.64(m, 2H), 4.50(m, 1H), 4.59(ABq, J=16Hz, Δν=70Hz, 3/5•2H), 4.64(s, 2/5•2H), 6.78(t, J=7Hz, 1H), 6.91(d, J=8Hz, 2H), 6.98(t, J=7Hz, 1H), 7.02- 7.10(m, 2H), 7.12(m, 1H), 7.16-7.37(m, 5H), 7.44(m, 1H), 7.50-7.62(m, 2/5•1H+ 1H), 7.75(d, J=8Hz, 3/5•1H), 10.83(br s, 1H) 14 MeCO 2-Me 538 CDCl₃ 2.06(s, 3H), 2.21(s, C₃₃H₃₉N₅O₂ 73.71 7.31 13.02 (M + 1⁺) 3H), 2.1-2.6(m, 2H), 2.9-3.3 74.00 7.37 13.21 (m, 12H), 3.58(m, 1H), 4.4- 4.6(m, 2H), 6.8-7.0(m, 5H), 7.0-7.4(m, 9H), 7.62(d, J=7 Hz, 1H), 8.15(br s, 1H) 15 MeCO 2-CF₃ foam 592 CDCl₃ 2.03(s, 3H), 2.15- C₃₃H₃₆F₃N₅O₂ 66.99 6.13 11.84 (M + 1⁺) 2.80(m, 5H), 2.80-3.73(m, 66.83 6.20 12.10 8H), 3.88(m, 1H), 4.47-4.93 (m, 3H), 6.72-7.03(m, 4H), 7.03-7.45(m, 7H), 7.45-7.76 (m, 4H), 8.22(br s, 1H) 16 MeCO 2-NO₂ foam 569 CDCl₃ 2.05(s, 3H), 2.28(m, C₃₂H₃₆N₆O₄ 67.59 6.38 14.78 (M + 1⁺) 1H), 2.3-2.7(m, 4H), 2.8-3.2 67.32 6.35 14.56 (m, 8H), 3.2-3.9(m, 2H), 4.58(m, 1H), 4.97(m, 1H), 6.8-7.0(m, 2H), 7.0-7.5(m, 10H), 7.5-7.7(m, 2H), 8.12 (d, J=7Hz, 1H), 8.15(br s, 1H) 17 MeCO 2-OMe foam 553 (M⁺) DMSO-d₆ 3:2 mixture of C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 (RS) amide rotamers 1.97(s, 71.50 7.18 12.73 1.8H), 2.07(s, 1.2H), 2.26- 2.50(m, 4H), 2.70-2.96(m, 4H), 2.96-3.16(m, 4H), 3.16- 3.65(m, 2H), 3.72(s, 2/5•3H), 3.74(s, 3/5•3H), 4.40(m, 1H), 4.42(ABq, J=18Hz, Δν=30Hz, 3/5•2H), 4.46(ABq, J=16 Hz, Δν=62Hz, 2/5•2H), 6.70-7.03(m, 7H), 7.03-7.13 (m, 2H), 7.13-7.29(m, 3H), 7.34(d, J=8Hz, 1H), 7.49- 7.62(m, 3/5H+1H), 7.72(d, J=6Hz, 2/5H), 10.93(br s, 1H) 18 MeCO 2-OMe foam 553 (M⁺) CDCl₃ 2.11(s, 3H), 2.41- C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 (R) Exact 2.43(m, 2H), 2.50-2.55(m, 72.19 7.25 12.93 Mass FAB 2H), 2.87-3.18(m, 9H), 3.78 (M + 1): (s, 3H), 4.02(dd, J=10, 14 calc.: Hz, 1H), 4.51(ABq, J=17 554.3131 Hz, Δν=42Hz, 2H), 4.59(m, found: 1H), 6.80-6.98(m, 6H), 7.07- 554.3144 7.45(m, 8H), 7.68(d, J=8 Hz, 1H), 8.14(s, 1H) 19 MeCO 2-OMe foam 553 (M⁺) DMSO-d₆ 3:2 mixture of C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 (S) amide rotamers 1.97(s, 71.62 7.28 12.38 3/5•3), 2.07(s, 2/5•3H), 2.23-2.60(m, 4H), 2.71-2.95 (m, 4H), 2.95-3.17(m, 4H), 3.17-3.80(m, 2H), 3.71(s, 3/5•2H), 3.74(s, 3/5•3H), 4.26(m, 1H), 4.44(ABq, J=16Hz, Δν=26Hz, 3/5•2H), 4.45(ABq, J=16 Hz, Δν=60Hz, 2/5•2H), 6.70-7.02(m, 7H), 7.02-7.12 (m, 2H), 7.12-7.30(m, 3H), 7.34(d, J=8Hz, 1H), 7.56 (d, J=10Hz, 3/5H+1H), 7.70 (d, J=10Hz, 2/5•1H), 10.82 (br s, 1H) 20 MeCO 3-F 86-88 541 (M⁺) CDCl₃ 2.09(s, 3H), 2.23(m, 1H), 2.3-2.7(m, 2H), 2.7-3.2 (m, 8H), 3.30(m, 1H), 3.60 (m, 1H), 4.02(m, 1H), 4.2- 4.7(m, 3H), 6.7-7.0(m, 6H), 7.0-7.5(m, 8H), 7.66(d, J=7 Hz, 1H), 8.16(br s, 1H) 21 MeCO 3-OMe foam 553 (M⁺) CDCl₃ 2.08(s, 3H), 2.15- C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 2.63(m, 4H), 2.72-3.27(m, 71.32 7.01 12.65 8H), 3.75(m, 1H), 3.78(s, 3H), 4.04(m, 1H), 4.51 (ABq, J=16Hz, Δν=46Hz, 2H), 4.56(m, 1H), 6.60-6.70 (m, 2H), 6.72-6.94(m, 5H), 7.04-7.46(m, 7H), 7.65(d, J=8Hz, 1H), 8.04(br s, 1H) 22 MeCO 4-OMe foam 553 (M⁺) DMSO-d₆ 1:1 mixture of C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 amide rotamers 2.01(s, 71.85 7.24 12.65 1/2•3H), 2.05(s, 1/2•3H), 2.23-2.60(m, 4H), 2.74-3.30 (m, 8H), 3.69(m, 1H), 3.72 (s, 1/2•3H), 3.74(s, 1/2•3H), 4.23(ABq, J=16 Hz, Δν=42Hz, 1/2•2H), 4.52 (m, 1H), 4.36(ABq, J=14 Hz, Δν=164Hz, 1/2•2H), 6.70-7.16(m, 10H), 7.24(m, 2H), 7.35(m, 1H), 7.55(m, 1/2•1H+1H), 7.73(m, 1/2•1H), 10.84(br s, 1H) 23 MeCO 4-SMe dec 569 (M⁺) CDCl₃ 2.09(s, 3H), 2.1-2.6 C₃₃H₃₉N₅O₂S 69.57 6.90 12.29 138 (m, 3H), 2.46(s, 3H), 2.8-3.1 69.86 6.93 12.33 (m, 8H), 3.30(m, 1H), 3.55 (m, 1H), 3.98(m, 1H), 4.47 (ABq, J=12Hz, Δν=52Hz, 2H), 4.58(m, 1H), 6.8-6.9 (m, 3H), 6.95(d, J=8Hz, 2H), 7.0-7.4(m, 9H), 7.66(d, J=8Hz, 1H), 8.08(br s, 1H) 24 HCO 2-OMe foam 540 (M + 1) CDCl₃ 2.33-2.47(m, 2H), C₃₂H₃₇N₅O₃ 71.21 6.91 12.98 2.50-2.65(m, 2H), 2.87-3.10 70.99 6.96 13.25 (m, 9H), 3.75(s, 3H), 3.77 (m, 1H), 4.40(ABq, J=15 Hz, Δν=35Hz, 2H), 4.65(m, 1H), 6.75-6.95(m, 6H), 7.03- 7.42(m, 8H), 7.67(d, J=9 Hz, 1H), 8.20(br s, 1H), 8.33(s, 1H) 25 BrCH₂CO 2-OMe foam 631, 633 CDCl₃ 2.37-2.47(m, 2H), C₃₃H₃₈BrN₅O₃ (M⁺'s for 2.53-2.63(m, 2H), 2.90-3.17 Br (m, 8H), 3.80(s, 3H), 3.95- isotopes) 4.13(m, 2H), 3.98(ABq, Exact J=11Hz, Δν=61Hz, 2H), Mass FAB 4.57(ABq, J=18Hz, Δν=80 (M + 1): Hz, 2H), 4.67(m, 1H), 6.78 calc.: (d, J=5Hz, 1H), 6.80-6.90 632.2236 (m, 4H), 7.07(d, J=3Hz, found: 1H), 7.10-7.30(m, 6H), 7.37 632.2213 (d, J=8Hz, 1H), 7.50(d, J=10Hz, 1H), 7.70(d, J=9 Hz, 1H), 8.07(s, 1H) 26 EtCO 2-OMe oil 568 CDCl₃ 1.12(t, J=9Hz, 3H), C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 (M + 1⁺) 2.38(q, J=9Hz, 2H), 2.33- 72.17 7.42 12.10 2.60(m, 4H), 2.83-3.13(m, 8H), 3.22(br d, J=13Hz, 1H), 3.80(s, 3H), 4.03(br t, J=13Hz, 1H), 4.55(ABq, J=20Hz, Δν=40Hz, 2H), 4.60(m, 1H), 6.83-6.97(m, 6H), 7.10-7.57(m, 8H), 7.68 (d, J=8Hz, 1H), 8.24(br s, 1H) 27 PhCO 2-OMe foam 615 (M⁺) CDCl₃ 2.28-2.57(m, 4H), C₃₈H₄₁N₅O₃ 74.12 6.71 11.37 2.77-3.17(m, 9H), 3.65(s, 74.38 6.87 11.32 3H), 4.22(t, J=13Hz, 1H), 4.60(ABq, J=15Hz, Δν=30 Hz, 2H), 4.82(m, 1H), 6.70- 6.92(m, 5H), 7.02-7.55(m, 14H), 7.68(d, J=7Hz, 1H), 8.22(br s, 1H) 28 EtOCO 2-OMe foam 584 (M + 1) DMSO-d₆ 1.05(t, J=8Hz, C₃₄H₄₁N₅O₄ 69.96 7.08 12.00 3H), 2.31-2.45(m, 4H), 69.85 7.19 11.98 2.73-2.90(m, 4H), 2.93-3.10 (m, 4H), 3.22-3.48(m, 2H), 3.66(s, 3H), 3.87-4.03(m, 2H), 4.26-4.55(m, 3H), 6.77 (t, J=7Hz, 1H), 6.80-7.00 (m, 6H), 7.05(t, J=8Hz, 1H), 7.11(br s, 1H), 7.20(t, J=9Hz, 3H), 7.32(d, J=10 Hz, 1H), 7.52(br d, J=6Hz, 2H) 29 MeNHCO 2-OMe oil 568 (M⁺) DMSO-d₆ 2.32-2.46(m, 4H), C₃₃H₄₀N₆O₃ 69.69 7.09 14.78 2.55(d, J=5Hz, 3H), 2.78- 69.94 7.13 14.83 2.90(m, 4H), 2.96-3.10(m, 4H), 3.18(dd, J=5, 14Hz, 1H), 3.44(dd, J=8, 13Hz, 1H), 3.70(s, 3H), 4.30(m, 1H), 4.37(ABq, J=18Hz, Δν=42Hz, 2H), 6.32(br d, J=5Hz, 1H), 6.77(t, J=7 Hz, 1H), 6.82-7.00(m, 6H), 7.05(t, J=8Hz, 1H), 7.11(d, J=3Hz, 1H), 7.16-7.25(m, 3H), 7.32(d, J=9Hz, 1H), 7.53(d, J=8Hz, 1H), 7.61 (d, J=9Hz, 1H), 10.82(br s, 1H) 30 MeO(OC)CH₂CO 2-OMe foam 611 (M⁺) CDCl₃ 2.37-2.47(m, 2H), C₃₅H₄₁N₅O₅ 68.72 6.76 11.45 2.50-2.60(m, 2H), 2.82-3.18 68.44 6.76 11.44 (m, 9H), 3.57(s, 2H), 3.72 (s, 3H), 3.78(s, 3H), 4.02 (dd, J=10, 14Hz, 1H), 4.47 (ABq, J=20Hz, Δν=40Hz, 2H), 4.60(m, 1H), 6.77-6.92 (m, 6H), 7.03-7.30(m, 6H), 7.37(d, J=7Hz, 1H), 7.45 (d, J=10Hz, 1H), 7.68(d, J=9Hz, 1H), 8.12(s, 1H) 31 HO(OC)CH₂CO 2-OMe 103-107 598 CDCl₃ 2.68-2.90(m, 4H), C₃₄H₃₉N₅O₅ (M + 1⁺) 2.90-3.37(m, 9H), 3.57(br s, Exact 2H), 3.78(s, 3H), 3.93(t, Mass FAB J=12Hz, 1H), 4.53(ABq, (M + 1): J=17Hz, Δν=47Hz, 2H), calc.: 4.70(m, 1H), 6.77-6.97(m, 598.3029 6H), 7.07-7.33(m, 7H), 7.37 found: (d, J=8Hz, 1H), 7.63(d, J=8 598.3046 Hz, 1H), 7.85(br s, 1H), 8.33(br s, 1H) 32 Me(CO)OCH₂CO 2-OMe foam 612 CDCl₃ 2.10(s, 3H), 2.35- C₃₅H₄₁N₅O₅ 68.72 6.76 11.45 (M + 1⁺) 2.43(m, 2H), 2.47-2.57(m, 68.50 6.86 11.20 2H), 2.90-3.13(m, 9H), 3.80 (s, 3H), 4.03(dd, J=10, 15 Hz, 1H), 4.40(ABq, J=19 Hz, Δν=30Hz, 2H), 4.57(m, 1H), 4.85(ABq, J=15Hz, Δν=19Hz, 2H), 6.75-6.90 (m, 6H), 7.03(d, J=2Hz, 1H), 7.10-7.30(m, 5H), 7.35- 7.43(m, 2H), 7.66(d, J=9 Hz, 1H), 8.32(br s, 1H) 33 HOCH₂CO 2-OMe foam 569 (M⁺) CDCl₃ 2.35-2.57(m, 4H), C₃₃H₃₉N₅O₄. 68.49 6.97 12.10 2.80-3.17(m, 9H), 3.52(t, 0.5H₂O 68.51 6.86 11.91 J=5Hz, 1H), 3.75(s, 3H), 4.08(m, 1H), 4.27(dd, J=5, 10Hz, 2H), 4.33(d, J=5Hz, 2H), 4.63(m, 1H), 6.73-6.92 (m, 6H), 7.03(d, J=3Hz, 1H), 7.12-7.32(m, 5H), 7.33- 7.40(m, 2H), 7.67(d, J=10 Hz, 1H), 8.07(br s, 1H) 34 H₂NCH₂CO 2-OMe foam 568 (M⁺) CDCl₃ 2.20(m, 2H), 2.35- C₃₃H₄₀N₆O₃ 69.69 7.09 14.78 2.45(m, 2H), 2.45-2.53(m, 69.82 7.14 14.49 2H), 2.80-3.07(m, 8H), 3.30 (dd, J=5, 15Hz, 1H), 3.47- 3.57(m, 2H), 3.77(s, 3H), 3.93(dd, J=10, 15Hz, 1H), 4.42(ABq, J=20Hz, Δν=30 Hz, 2H), 4.62(m, 1H), 6.77- 6.90(m, 5H), 7.03-7.40(m, 9H), 7.65(d, J=8Hz, 1H), 8.12(br s, 1H) 35 Me₂NCH₂CO 2-OMe foam 596 (M⁺) CDCl₃ 2.30(s, 6H), 2.32- C₃₅H₄₄N₆O₃ 70.44 7.43 14.08 2.50(m, 4H), 2.87-3.05(m, 70.15 7.39 14.02 8H), 3.20(s, 2H), 3.33(dd, J=6, 9Hz, 1H), 3.78(s, 3H), 3.85(m, 1H), 4.58(m, 1H) 4.65(ABq, J=18Hz, Δν=42 Hz, 2H), 6.81-6.93(m, 6H), 7.10-7.40(m, 8H), 7.65(d, J=11Hz, 1H), 8.17(br s, 1H) 36 t-Bu— 2-OMe foam 668 (M⁺) CDCl₃ 1.43(s, 9H), 2.33- C₃₈H₄₈N₆O₅ 68.24 7.23 12.57 O(CO)NH— 2.57(m, 4H), 2.82-3.12(m, 68.44 7.50 12.61 CH₂CO 8H), 3.17(dd, J=5, 15Hz, 1H), 3.77(s, 3H), 3.93-4.10 (m, 3H), 4.42(ABq, J=18 Hz, Δν=41Hz, 2H), 4.60(m, 1H), 5.50(br s, 1H), 6.73- 6.92(m, 6H), 7.05(s, 1H), 7.08-7.32(m, 5H), 7.35(d, J=10Hz, 2H), 7.65(d, J=10 Hz, 1H), 8.10(br s, 1H) 37 MeSO₂ 2-OMe foam 589 (M⁺) DMSO-d₆ 2.28-2.46(m, 4H), C₃₂H₃₉N₅O₄S 65.17 6.67 11.88 2.83(d, J=7Hz, 4H), 2.90(s, 64.88 6.72 11.60 3H), 2.98-3.04(m, 4H), 3.26- 3.34(m, 2H), 3.67(s, 3H), 4.30(m, 1H), 4.36(d, J=5 Hz, 2H), 6.77(t, J=8Hz, 1H), 6.84-6.92(m, 3H), 6.92- 7.00(m, 2H), 7.03-7.09(m, 2H), 7.18-7.30(m, 4H), 7.33 (d, J=8Hz, 1H), 7.46(d, J=8 Hz, 1H), 7.54(d, J=9Hz, 1H), 10.82(br s, 1H)

Analysis Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 38 Me 128-129 447 (M⁺) CDCl₃ 2.07(s, 3H), 2.38-2.78 C₂₆H₃₃N₅O₂ 69.77 7.43 15.65 (m, 3H), 2.8-3.3(m, 11H), 69.59 7.52 15.65 3.42(m, 1H), 3.67(m, 1H), 3.95(m, 1H), 4.58(m, 1H), 6.8-7.0(m, 3H), 7.1-7.4(m, 7H), 7.68(d, J=7Hz, 1H), 8.21 (br s, 1H) 39 n-Bu foam 489 (M⁺) ¹H CDCl₃ 0.88(t, J=6Hz, 3H), C₂₉H₃₉N₅O₂ 71.13 8.03 14.30 1.1-1.40(m, 2H), 1.4-1.6(m, 71.40 8.05 14.41 2H), 2.08(s, 3H), 2.2-2.4(m, 4H), 2.8-3.1(m, 8H), 3.1-3.4 (m, 3H), 3.9(m, 1H), 4.5(br s, 1H), 6.8-7.0(m, 3H), 7.0-7.5 (m, 7H), 7.68(d, J=6Hz, 1H), 8.31(br s, 1H). 40 n-Hex foam 517 (M⁺) ¹H CDCl₃ 0.82-0.92(m, 3H), C₃₁H₄₃N₅O₂ 71.92 8.37 13.53 1.12-1.36(m, 6H), 1.40-1.70 71.85 8.35 13.59 (m, 3H), 2.05(s, 3H), 2.31-2.61 (m, 3H), 2.80-3.11(m, 8H), 3.11-3.42(m, 3H), 3.9(m, 1H), 4.5(m, 1H), 6.75-6.98(m, 3H), 7.08-7.48(m, 7H), 7.7(m, 1H), 8.1(brs, 1H). 41 (c-hexyl)CH₂ foam 530 CDCl₃ 0.65-1.02(m, 2H), 1.02- C₃₂H₄₃N₅O₂ 72.56 8.18 13.22 (M + 1⁺) 1.36(m, 3H), 1.36-1.87(m, 72.46 8.12 13.07 9H), 2.07(s, 3H), 2.15-3.70(m, 12H), 3.95(m, 1H), 4.57(m, 1H), 6.70-7.03(m, 4H), 7.03- 7.23(m, 4H), 7.31-7.44(m, 2H), 7.69(d, J=10Hz, 1H), 8.16 (br s, 1H) 42 Ph 183-184 509 (M⁺) ¹H DMSO 1.71(s, 3H), 2.23- C₃₁H₃₅N₅O₂ 73.04 6.92 13.74 2.43(m, 4H), 2.71-2.94(m, 4H), 73.30 7.11 13.73 2.94-3.10(m, 4H), 3.61(m, 1H), 4.03(m, 1H), 4.24(m, 1H), 6.77 (t, J=8Hz, 1H), 6.92-6.99(m, 3H), 6.99-7.12(m, 2H), 7.21(t, J=8Hz, 2H), 7.24-7.35(m, 3H), 7.4(m, 1H), 7.40-7.54(m, 4H), 10.92(brs, 1H). 43 PhCH₂CH₂ 537 (M⁺) ¹H DMSO (3:2 mixture of amide C₃₃H₃₉N₅O₂ 73.71 7.31 13.02 rotamers) 1.69(s, 3/5•3H), 2.00 73.95 7.45 13.07 (s, 2/5•3H), 2.50-2.60(m, 5H), 2.70-3.05(m, 5H), 3.05-3.19 (m, 4H), 3.19-3.36(m, 2H), 3.36-3.64(m, 2H), 4.32(m, 1H), 6.76(t, J=8Hz, 1H), 6.90(d, J=8Hz, 2H), 6.95-7.39(m, 11H), 7.56(m, 1H), 7.76(m, 2/5•1H), 7.92(m, 3/5•1H), 10.81(br s, 2/5•1H), 10.85(br s, 3/5•1H).

Analysis % Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 44 H 2-OMe (R) foam 517 (M⁺) CDCl₃ 1.10-2.18(m, 12H), C₃₁H₄₃N₅O₂ 71.92 8.37 13.53 2.18-3.18(m, 14H), 3.61-3.95 71.69 8.25 13.26 (m, 2H), 3.93(s, 3H), 4.36(m, 1H), 6.76-6.96(m, 3H), 7.04- 7.44(m, 5H), 7.42(d, J=8Hz, 1H), 7.65(d, J=8Hz, 1H), 9.13 (br s, 1H) 45 H 2-OMe (S) foam 517 (M⁺) CDCl₃ 1.13-2.18(m, 12H), C₃₁H₄₃N₅O₂ 71.92 8.37 13.53 2.18-3.33(m, 14H), 3.61-3.96 71.91 8.25 13.42 (m, 2H), 3.85(s, 3H), 4.36(m, 1H), 6.80-6.97(m, 3H), 6.97- 7.36(m, 6H), 7.44(d, J=8Hz, 1H), 9.60(br s, 1H) 46 MeCO H foam 530 CDCl₃ 3:1 mixture of amide C₃₂H₄₃N₅O₂ 72.56 8.18 13.22 (M + 1⁺) rotamers 1.21-1.69(m, 10H), 72.36 8.17 13.12 1.90-2.19(m, 3H), 2.07(s, 3/4•3H), 2.10(s, 1/4•3H), 2.37-2.55(m, 5H), 2.65-3.18 (m, 6H), 4.02(dd, J=13Hz, J= 10Hz, 1H), 4.50(ABq, J=17Hz, Δν=52Hz, 3/4•2H), 4.67(ABq, J=17Hz, Δν=228Hz, 1/4•2H), 4.55(m, 1H), 6.94-7.44(m, 10H), 7.65(d, J=8Hz, 3/4•1H), 7.53(d, J=8Hz, 1/4•1H), 8.08 (br s, 3/4•1H), 8.22(br s, 1/4•1H). 47 MeCO 2-Cl (RS) foam 563 (M⁺) CDCl₃ 1.17-1.80(m, 10H), C₃₂H₄₂ClN₅O₂ Exact 1.90-2.27(m, 3H), 2.03(s, 3H), Mass 2.35-2.59(m, 5H), 2.67-3.23 FAB (m, 6H), 3.97(dd, J=10, 15Hz, theory: 1H), 4.53(m, 1H), 4.58(ABq, 564.3105 J=17Hz, Δν=21Hz, 2H), 6.95- found: 7.29(m, 6H), 7.34(d, J=8Hz, 564.3130 2H), 7.42(d, J=9Hz, 1H), 7.63 (M⁺¹) (d, J=8Hz, 1H), 8.19(br s, 1H) 48 MeCO 2-Cl (R) foam 563 (M⁺) ¹H CDCl₃ 1.1-1.8(m, 10H), C₃₂H₄₂ClN₅O₂ 68.13 7.50 12.41 1.8-2.3(m, 4H), 2.04(s, 3H), 68.20 7.60 12.17 2.4-2.6(m, 3H), 2.6-2.8(m, 2H), 2.8-2.9(m, 2H), 2.9-3.1 (m, 2H), 3.2(m, 1H), 3.9(m, 1H), 4.5-4.7(m, 3H), 7.0-7.6 (m, 9H), 7.62(d, J=6Hz, 1H), 8.32(br s, 1H). 49 MeCO 2-Cl (S) foam 563 (M⁺) ¹H CDCl₃ 1.3-1.8(m, 6H), C₃₂H₄₂ClN₅O₂ 68.13 7.50 12.41 2.04(s, 3H), 1.8-2.1(m, 3H), 68.40 7.61 12.60 2.1-2.3(m, 3H), 2.4-2.6(m, 5H), 2.7-2.8(m, 2H), 2.86(d, J=2Hz, 2H), 2.9-3.1(m, 2H), 3.2(m, 1H), 3.9(m, 1H), 4.5- 4.7(m, 3H), 7.0-7.5(m, 9H), 7.63(d, J=7Hz, 1H), 8.38(br s, 1H) 50 MeCO 2-OMe (RS) foam 559 (M⁺) CDCl₃ 1.30-1.86(m, 10H), C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 1.93-2.32(m, 3H), 2.10(s, 3H), 70.95 8.05 12.45 2.45-2.67(m, 4H), 2.71-3.18 (m, 5H), 2.87(s, 2H), 3.76(s, 3H), 3.99(dd, J=14Hz, J=10Hz, 1H), 4.49(ABq, J=17Hz, Δν= 41Hz, 2H), 4.55(m, 1H), 6.79- 6.93(m, 3H), 7.06-7.27(m, 4H), 7.36(d, J=8Hz, 1H), 7.45(d, J=9Hz, 1H), 7.66(d, J=8Hz, 1H), 8.28(br s, 1H) 51 MeCO 2-OMe (R) 559 (M⁺) DMSO-d₆ 3:2 mixture of amide C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 rotamers, 1.25-1.70(m, 10H), 70.57 8.05 12.39 1.77-2.00(m, 3H), 1.95(s, 3/5•3H), 2.04(s, 2/5•3H), 2.10-2.97(m, 9H), 3.10-3.65 (m, 3H), 3.72(s, 2/5•3H), 3.74 (s, 3/5•3H), 4.26-4.58(m, 3H), 6.76-7.12(m, 6H), 7.13-7.35(m, 2H), 7.42-7.66(m, 2H), 10.80 (br s, 1H) 52 MeCO 2-OMe (S) 559 (M⁺) DMSO-d₆ 3:2 mixt. of amide C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 rotamers, 1.15-1.68(m, 10H), 71.01 8.39 12.63 1.68-2.20(m, 3H), 1.95(s, 3/5•3H), 2.04(s, 2/5•3H), 2.20-3.00(m, 9H), 3.00-3.65 (m, 3H), 3.74(s, 2/5•3H), 3.76 (s, 3/5•3H), 4.20-4.60(m, 3H), 6.75-7.15(m, 6H), 7.15-7.40(m, 2H), 7.40-7.68(m, 2H), 10.78 (br s, 1H)

Analysis, % Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 53 Ph 140-141 515 (M⁺) ¹H DMSO 1.21-1.58(m, 10H), C₃₁H₄₁N₅O₂ 72.20 8.01 13.58 1.70(s, 3H), 1.87(ABq, J=8Hz, 71.98 8.07 13.53 Δν=20Hz, 2H), 2.04(m, 1H), 2.29-2.49(m, 4H), 2.45-2.64(m, 2H), 2.63-2.79(m, 2H), 2.79- 2.95(m, 2H), 3.58(m, 1H), 4.02 (t, J=12Hz, 1H), 4.20(m, 1H), 6.93(t, J=8Hz, 1H), 6.98-7.11 (m, 2H), 7.17-7.53(m, 8H), 10.91(br s, 1H). 54 PhCH₂CH₂ foam 543 (M⁺) ¹H DMSO (3:2 mixture of amide C₃₃H₄₅N₅O₂ 72.89 8.34 12.88 rotamers) 1.23-1.57(m, 10H), 72.60 8.29 12.64 1.75-1.97(m, 2H), 1.84(s, 3/5•3H), 1.93(s, 2/5•3H), 2.05(m, 1H), 2.23-2.47(m, 4H), 2.50-2.77(m, 6H), 2.77-2.95 (m, 2H), 3.20-3.35(m, 1H), 3.36-3.52(m, 2H), 3.62(m, 1H), 4.39(m, 1H), 6.97(m, 1H), 7.02-7.31(m, 7H), 7.34(d, J=8Hz, 1H), 7.45(d, J=8Hz, 3/5H), 7.53-7.67(m, 2/5•1H+ 1H), 10.84(br s, 1H).

Analysis, % Example Mp, Theory/Found No. R ° C. MS ¹H NMR Formula C H N 55 Br (R) foam 473 (M⁺) CDCl₃ 2.15(s, 3H), 2.81-2.96 C₂₃H₂₆N₃O₃₂Br 58.48 5.55  8.90 (m, 2H), 3.15(AB_(q), J=4.3Hz, 58.69 5.66  8.94 Δν=14.6Hz, 1H), 3.72(s, 3H), 3.79(s, 2H), 4.06-4.15(m, 1H), 4.30(m, 1H), 4.38(AB_(q), J= 16.7Hz, Δν=49.0Hz, 2H), 6.72-6.81(m, 3H), 7.01(s, 1H), 7.13-7.30(m, 3H), 7.35-7.41 (m, 2H), 7.71(d, J=7.8Hz, 1H), 8.04.1H). 56 PhO foam 485 (M⁺) CDCl₃ 2.00(s, 3H), 2.86(dd, C₂₉H₃₁N₃O₄ 71.73 6.43  8.65 J=8, 14Hz, 1H), 3.01(dd, J=5, 71.48 6.59  8.46 14Hz, 1H), 3.20(dd, J=5, 15Hz, 1H), 3.70(s, 3H), 4.04(dd, J=10, 14Hz, 1H), 4.34(ABq, J=18Hz, Δν=44Hz, 2H), 4.44(ABq, J=15Hz, Δν=25Hz, 2H), 4.42(m, 1H), 6.70-6.85(m, 3H), 6.85-7.06(m, 4H), 7.06-7.45 (m, 6H), 7.54(m, 1H), 7.71(d, J=8Hz, 1H), 7.97(br s, 1H) 57 PhS foam 501 (M⁺) CDCl₃ 1.92(s, 3H), 2.76(dd, C₂₉H₃₁N₃O₃S 69.44 6.23  8.38 J=8, 14Hz, 1H), 2.92(dd, J=4, 69.55 6.49  8.10 14Hz, 1H), 3.06(dd, J=4, 14Hz, 1H), 3.57(s, 2H), 3.69(s, 3H), 3.99(dd, J=8, 14Hz, 1H), 4.29 (ABq, J=16Hz, Δν=44Hz, 2H), 4.36(m, 1H), 6.65(m, 3H), 6.85 (d, J=3Hz, 1H), 7.05-7.37(m, 9H), 7.42(m, 1H), 7.67(d, J= 8Hz, 1H), 7.85(br s, 1H) 58 PhNHCH₂CH₂NH foam 528 CDCl₃ 2.11(s, 3H), 2.72-2.95 C₃₁H₃₇N₅O₃ 70.56 7.07 13.27 (M + 1⁺) (m, 4H), 3.00-3.34(m, 6H), 3.72 70.35 7.03 13.06 (s, 3H), 4.14(dd, J=11, 13Hz, 1H), 4.40(ABq, J=17Hz, Δν= 63Hz, 2H), 4.42(m, 1H), 4.78 (br s, 1H), 6.65-6.84(m, 6H), 6.95(d, J=3Hz, 1H), 7.07- 7.35(m, 6H), 7.67(d, J=8Hz, 1H), 7.80-7.91(m, 2H). 59 1-pyrrolidinyl foam 463 CDCl₃ 1.66-1.74(m, 4H), 2.11 C₂₇H₃₄N₄O₃ 70.10 7.41 12.11 (M + 1⁺) (s, 3H), 2.47(m, J=19Hz, 4H), 70.42 7.29 11.75 2.86-3.17(m, 5H), 3.74(s, 3H), 4.00(dd, J=11, 14Hz, 1H), 4.46 (ABq, J=17Hz, Δν=46Hz, 2H), 4.52(br s, 1H), 6.76-6.83(m, 2H), 7.08-7.28(m, 3H), 7.18(s, 1H), 7.35(d, J=8Hz, 1H), 7.52 (d, J=8Hz, 1H), 7.69(d, J=8Hz, 1H), 8.38(br s, 1H) 60 1-piperidinyl foam 476 (M⁺) CDCl₃ 1.37-1.56(m, 6H), C₂₈H₃₆N₄O₃ 70.56 7.61 11.58 2.09(s, 3H), 2.30(br s, 4H), 70.68 7.70 11.58 2.80-3.19(m, 5H), 3.75(s, 3H), 3.95(dd, J=11, 13Hz, 1H), 4.46 (ABq, J=17Hz, Δν=44Hz, 2H), 4.53(m, 1H), 6.75-6.88(m, 3H), 7.04-7.24(m, 5H), 7.34(d, J= 8Hz, 1H), 7.68(d, J=7Hz, 1H), 8.04(br s, 1H) 61 1-hexamethyleneiminyl foam 490 (M⁺) CDCl₃ 1.52(br s, 8H), 2.09(s, C₂₉H₃₈N₄O₃ 70.99 7.81 11.42 3H), 2.54(br s, 4H), 2.87-3.10 71.27 7.98 11.39 (m, 4H), 3.21(dd, J=5, 13Hz, 1H), 3.76(s, 3H), 3.92(dd, J=10, 13Hz, 1H), 4.48(ABq, J=17Hz, Δν=41Hz, 2H), 4.53 (m, 1H), 6.73-6.89(m, 3H), 7.04-7.25(m, 4H), 7.34(d, J= 6Hz, 1H), 7.58(m, 1H), 7.66(d, J=7Hz, 1H), 8.04(br s, 1H) 62 4-morpholinyl foam 478 (M⁺) CDCl₃ 2.07(s, 3H), 2.20-2.29 C₂₇H₃₄N₄O₄ 67.76 7.16 11.71 (m, 2H), 2.31-2.41(m, 2H), 67.54 7.18 11.58 2.85-2.97(m, 3H), 3.01-3.13 (m, 2H), 3.46-3.67(m, 4H), 3.77 (s, 3H), 4.15(dd, J=10, 13Hz, 1H), 4.47(ABq, J=17Hz, Δν= 48Hz, 2H), 4.52(m, 1H), 6.77- 6.89(m, 3H), 7.02-7.28(m, 4H), 7.36(d, J=6Hz, 1H), 7.46(d, J=8Hz, 1H), 7.68(d, J=7Hz, 1H), 8.02(br s, 1H) 63 1-indolinyl foam 510 (M⁺) CDCl₃ 1.85(s, 3H), 2.85-3.41 C₃₁H₃₄N₄O₃ 72.92 6.71 10.97 (m, 7H), 3.60(ABq, J=17Hz, 73.21 6.54 11.03 Δν=42Hz, 2H), 3.73(s, 3H), 4.00(dd, J=12, 13Hz, 1H), 4.38 (ABq, J=17Hz, Δν=48Hz, 2H), 4.43-4.48(m, 1H), 6.32(d, J=8 Hz, 1H), 6.76(m, 3H), 6.97- 7.24(m, 7H), 7.35(d, J=8Hz, 1H), 7.54(d, J=8Hz, 1H), 7.70 (d, J=8Hz, 1H), 7.99(br s, 1H) 64 1,2,3,4- foam 524 (M⁺), CDCl₃ 2.06(s, 3H), 2.61-3.28 C₃₂H₃₆N₄O₃ 73.26 6.92 10.68 tetrahydroisoquinolin-4-yl 525 (m, 9H), 3.48-3.94(m, 3H), 3.77 73.31 6.95 10.43 (M + 1⁺) (s, 3H), 4.50(ABq, J=17Hz, Δν=36Hz, 2H), 4.57(m, 1H), 6.78-6.92(m, 4H), 6.98-7.26(m, 8H), 7.34(d, J=9Hz, 1H), 7.62 (d, J=8Hz, 1H), 7.98(br s, 1H) 65 1-(4-Ph-piperidinyl) foam 552 (M⁺) CDCl₃ 1.50-1.91(m, 4H), 2.08 C₃₄H₄₀N₄O₃ 73.89 7.30 10.14 (s, 3H), 2.06-2.22(m, 2H), 2.40 73.69 7.25 10.31 (m, 1H), 2.64(br d, J=11Hz, 1H), 2.80(br d, J=12Hz, 1H), 2.86-2.98(m, 3H), 3.04-3.18 (m, 2H), 3.73(s, 3H), 4.01(dd, J=10, 14Hz, 1H), 4.46(ABq, J=17Hz, Δν=45Hz, 2H), 4.54 (m, 1H), 6.76-6.85(m, 3H), 7.02-7.36(m, 10H), 7.54(d, J= 8Hz, 1H), 7.70(d, J=8Hz, 1H), 8.01(br s, 1H) 66 1-(4-Me₂N-piperidinyl) foam 519 (M⁺) CDCl₃ 1.26(m, 1H), 1.48-1.76 C₃₀H₄₁N₅O₃ 69.34 7.95 13.48 (m, 3H), 1.90-2.11(m, 3H), 2.09 69.58 8.01 13.52 (s, 3H), 2.25(s, 6H), 2.51(br d, J=13Hz, 1H), 2.73(br d, J= 12Hz, 1H), 2.85(s, 2H), 2.85- 3.23(m, 3H), 3.75(s, 3H), 3.94 (dd, J=10, 14Hz, 1H), 4.47 (ABq, J=17Hz, Δν=43Hz, 2H), 4.51(m, 1H), 6.77-6.88(m, 3H), 7.01-7.28(m, 4H), 7.35(d, J=8Hz, 1H), 7.41(d, J=9Hz, 1H), 7.66(d, J=7Hz, 1H), 8.09 (br s, 1H) 67 1-(4-Ph-Δ³-piperidinyl) foam 550 (M⁺) CDCl₃ 2.12(s, 3H), 2.21-2.70 C₃₄H₃₈N₄O₃ 73.06 6.87  9.99 (m, 4H), 2.90-3.25(m, 7H), 3.77 73.03 6.95 10.03 (s, 3H), 3.95(dd, J=10, 14Hz, 1H), 4.52(ABq, J=17Hz, Δν= 38Hz, 2H), 4.61(m, 1H), 5.95 (br s, 1H), 6.85(m, 3H), 7.00- 7.54(m, 11H), 7.67(d, J=8Hz, 1H), 8.08(br s, 1H) 68 1-(4-AcNH-4-Ph-piperidinyl) foam 609 (M⁺) ¹H CDCl₃ 1.87-2.50(m, 7H), C₃₆H₄₃N₅O₄ 70.91 7.11 11.48 2.00(s, 3H), 2.07(s, 3H), 2.60 70.68 7.13 11.49 (m, 1H), 2.87-3.19(m, 5H), 3.73 (s, 3H), 4.06(dd, J=10, 14Hz, 1H), 4.46(ABq, J=17Hz, Δν= 47Hz, 2H), 4.52(m, 1H), 5.43 (br s, 1H), 6.75-6.90(m, 3H), 7.04-7.48(m, 10H), 7.56(d, J= 8Hz, 1H), 7.69(d, J=8Hz, 1H), 8.10(br s, 1H). 69 1-(4-(4-Cl—Ph)- foam 587 (M⁺) CDCl₃ 2.11(s, 3H), 2.20-2.42 C₃₃H₃₈N₅O₃Cl 67.39 6.51 11.91 piperazinyl) (m, 2H), 2.42-2.58(m, 2H), 67.10 6.77 12.11 2.82-3.20(m, 9H), 3.76(s, 3H), 4.01(m, 1H), 4.50(ABq, J= 16Hz, Δν=42Hz, 2H), 4.54(m, 1H), 6.68-6.90(m, 5H), 7.04-7.32(m, 6H), 7.35(d, J=8Hz, 1H), 7.40 (m, 1H), 7.66 (d, J=9Hz, 1H), 8.03(br s, 1H) 70 1-(4-(3-CF₃—Ph)- foam 621 (M⁺) CDCl₃ 2.10(s, 3H), 2.28-2.42 C₃₄H₃₈N₅O₃F₃ 65.69 6.16 11.27 piperazinyl) (m, 2H), 2.42-2.56(m, 2H), 65.47 6.28 11.34 2.84-3.20(m, 9H), 3.77(s, 3H), 4.01(m, 1H), 4.49(ABq, J= 18Hz, Δν=42Hz, 2H), 4.56(m, 1H), 6.76-6.90(m, 3H), 6.90-7.27(m, 7H), 7.28-7.46 (m, 3H), 7.66(d, J=7Hz, 1H), 8.06(br s, 1H) 71 1-(4-Me-piperazinyl) foam 492 CDCl₃ 2.09(s, 3H), 2.11-2.52 C₂₈H₃₇N₅O₃ (M + 1⁺) (m, 11H), 2.82-2.97(m, 3H), Exact Mass Data 2.99-3.15(m, 2H), 3.75(s, 3H), (M + 1) 4.01(dd, J=11, 14Hz, 1H), 4.45 Calc'd: 492.2975 (ABq, J=16Hz, Δν=46Hz, 2H), Meas: 492.2977 4.51(m, 1H), 6.76-6.88(m, 3H), 7.02-7.24(m, 4H), 7.34(d, J=8Hz, 1H), 7.41(d, J=8Hz, 1H), 7.68(d, J=8Hz, 1H), 8.01 (br s, 1H) 73 1-(4-i-Pr-piperazinyl) foam 519 (M⁺) CDCl₃ 1.07(br d, J=6Hz, 6H), C₃₀H₄₁N₅O₃ 69.34 7.95 13.48 2.08(s, 3H), 2.20-2.80(m, 9H), 69.60 8.09 13.49 2.83-3.16(m, 5H), 3.77(s, 3H), 4.00(dd, J=10, 14Hz, 1H), 4.47 (ABq, J=8Hz, Δν=42Hz, 2H), 4.53(m, 1H), 6.73-6.94(m, 3H), 6.94-7.30(m, 4H), 7.30-7.42(m, 2H), 7.65(d, J=10Hz, 1H), 8.06 (br s, 1H) 74 1-(4-cyclohexyl- foam 559 (M⁺) CDCl₃ 1.05-1.34(m, 6H), 1.55- C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 piperazinyl) (RS) 1.95(m, 4H), 2.09(s, 3H), 2.20- 71.10 8.28 12.53 2.60(m, 9H), 2.90(s, 2H), 2.85- 3.16(m, 3H), 3.77(s, 3H), 4.02 (dd, J=11, 13Hz, 1H), 4.47 (ABq, J=16Hz, Δν=44Hz, 2H), 4.54(m, 1H), 6.77-6.88(m, 3H), 7.05-7.25(m, 4H), 7.31- 7.42(m, 2H), 7.66(d, J=7Hz, 1H), 8.08(br s, 1H) 75 1-(4-cyclohexyl- foam 560 CDCl₃ 1.09-1.28(m, 5H), 1.64 C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 piperazinyl) (R) (M + 1⁺) (d, J=10Hz, 1H), 1.80-1.89(m, 70.71 8.21 12.42 4H), 2.10(s, 3H), 2.24-2.52(m, 9H), 2.90(s, 2H), 2.95(d, J=7Hz, 1H), 3.02(d, J=7Hz, 1H), 3.12 (dd, J=5, 14Hz, 1H), 3.77(s, 3H), 4.01(dd, J=10, 14Hz, 1H), 4.49(ABq, J=17Hz, Δν=43Hz, 2H), 4.56(m, 1H), 6.79-6.87(m, 3H), 7.05-7.24(m, 4H), 7.34- 7.41(m, 2H), 7.67(d, J=8Hz, 1H), 8.22(s, 1H) 76 1-(4-cyclohexyl- foam 559 (M⁺) ¹H CDCl₃ 1.05-1.31(m, 5H), C₃₃H₄₅N₅O₃ 70.81 8.10 12.51 piperazinyl) (S) 1.64(m, 1H), 1.75-1.90(m, 4H), 70.99 8.27 12.76 2.10(s, 3H), 2.24-2.52(m, 9H), 2.87(s, 2H), 2.95(d, J=7Hz, 1H), 3.01(d, J=7Hz, 1H), 3.12(dd, J=5, 14Hz, 1H), 3.77(s, 3H), 3.99(dd, J=10, 14Hz, 1H), 4.46(ABq, J=17Hz, Δν=43Hz, 2H), 4.56(m, 1H), 6.75-6.90(m, 3H), 7.05-7.24 (m, 4H), 7.34-7.41(m, 2H), 7.67(d, J=8Hz, 1H), 8.14(s, 1H) 77 1-(4-PhCH₂- foam 568 CDCl₃ 2.08(s, 3H), 2.16-2.62 C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 piperazinyl) (M + 1⁺) (m, 8H), 2.82-2.97(m, 3H), 72.15 7.37 12.56 2.99-3.18(m, 2H), 3.41-3.62 (m, 2H), 3.76(s, 3H), 4.02(dd, J=10, 13Hz, 1H), 4.49(ABq, J=18Hz, Δν=48Hz, 2H), 4.53(m, 1H), 6.76-6.88 (m, 3H), 7.06(d, J=3Hz, 1H), 7.06-7.45(m, 10H), 7.68(d, J=8Hz, 1H), 8.06(br s, 1H) 78 1-(4-(2-pyrimidinyl)- foam 555 (M⁺) CDCl₃ 2.11(s, 3H), 2.28-2.55 C₃₁H₃₇N₇O₃ 67.01 6.71 17.64 piperazinyl) (m, 4H), 2.88-3.12(m, 5H), 66.90 6.85 17.43 3.56-3.86(m, 4H), 3.77(s, 3H), 4.02(m, 1H), 4.47(ABq, J= 17Hz, Δν=41Hz, 2H), 4.52(m, 1H), 6.50(br s, 1H), 6.76-6.86(m, 3H), 7.04- 7.28(m, 4H), 7.36(d, J=7Hz, 1H), 7.61(br s, 1H), 7.67(d, J=7Hz, 1H), 8.10(br s, 1H), 8.30(d, J=5Hz, 2H) 79 1-(4-MeCO-piperazinyl) foam 519 (M⁺), CDCl₃ 2.04(s, 3H), 2.09(s, 3H), C₂₉H₃₇N₅O₄ 67.03 7.18 13.48 520 2.16-2.48(m, 4H), 2.86-3.11(m, 66.81 7.20 13.30 (M + 1⁺) 4H), 3.21-3.65(m, 5H), 3.78(s, 3H), 4.04(m, 1H), 4.46(ABq, J= 17Hz, Δν=26Hz, 2H), 4.50(m, 1H), 6.76-6.86(m, 3H), 7.02-7.28(m, 4H), 7.36(d, J= 7Hz, 1H), 7.50(br s, 1H), 7.66 (d, J=7Hz, 1H), 8.11(br s, 1H) 80 1-(4-EtO(CO)- foam 549 (M⁺) CDCl₃ 1.23(t, J=7Hz, 3H), C₃₀H₃₉N₅O₅ 65.55 7.15 12.74 piperazinyl) 2.08(s, 3H), 2.12-2.40(m, 4H), 65.29 7.19 12.59 2.85-2.97(m, 3H), 2.98-3.12 (m, 2H), 3.22-3.49(m, 4H), 3.75(s, 3H), 4.03(m, 1H), 4.11 (q, J=7Hz, 2H), 4.44(ABq, J=17Hz, Δν=45Hz, 2H), 4.48(m, 1H), 6.76-6.86 (m, 3H), 7.04-7.25(m, 4H), 7.34(d, J=8Hz, 1H), 7.46(br s, 1H), 7.66(d, J=8Hz, 1H), 8.04 (br s, 1H) 81 (2-pyridyl)CH₂NH foam 499 (M⁺) CDCl₃ 2.10(s, 3H), 2.91(m, 1H), C₂₉H₃₃N₅O₃ 69.72 6.66 14.02 3.00-3.16(m, 2H), 3.30(s, 2H), 69.75 6.84 13.88 3.65-3.88(m, 2H), 3.77(s, 3H), 4.01(dd, J=10, 16Hz, 1H), 4.46 (ABq, J=17Hz, Δν=53Hz, 2H), 4.54(m, 1H), 6.74-6.86(m, 2H), 7.02-7.28(m, 7H), 7.34(d, J=8Hz, 1H), 7.56-7.72(m, 3H), 8.06(br s, 1H), 8.55(d, J= 6Hz, 1H) 82 (3-pyridyl)CH₂NH foam 499 (M⁺) CDCl₃ 2.08(s, 3H), 2.90(dd, C₂₉H₃₃N₅O₃ 69.72 6.66 14.02 J=8, 15Hz, 1H), 2.97-3.10(m, 69.51 6.79 13.90 2H), 3.24(s, 2H), 3.69(ABq, J= 14Hz, Δν=25Hz, 2H), 3.74 (s, 3H), 4.04(dd, J=13, 16Hz, 1H), 4.45(ABq, J=18Hz, Δν=53Hz, 2H), 4.50(m, 1H), 6.74-6.87(m, 3H), 7.04(d, J=4Hz, 1H), 7.08-7.30(m, 4H), 7.35(d, J=8Hz, 1H), 7.49(d, J= 8Hz, 1H), 7.60-7.70(m, 2H), 8.12(br s, 1H), 8.48-8.52 (m, 2H) 83 (4-pyridyl)CH₂NH foam 499 (M⁺) CDCl₃ 2.09(s, 3H), 2.84-3.10 C₂₉H₃₃N₅O₃ 69.72 6.66 14.02 (m, 3H), 3.20(s, 2H), 3.65(ABq, 69.99 6.77 13.79 J=14Hz, Δν=25Hz, 2H), 3.72(s, 3H), 4.08(dd, J=12, 15Hz, 1H), 4.40(ABq, J=16Hz, Δν=51Hz, 2H), 4.48(m, 1H), 6.73-6.84(m, 3H), 7.00(d, J=3Hz, 1H), 7.08-7.25(m, 5H), 7.32(d, J=8Hz, 1H), 7.45(d, J=8Hz, 1H), 7.67(d, J=8Hz, 1H), 8.01(br s, 1H), 8.51(d, J=7Hz, 2H) 84 PhNHCOCH₂NH foam 541 (M⁺) ¹H DMSO (3:2 mixture of amide C₃₁H₃₅N₅O₄ 68.74 6.51 12.93 rotamers) 1.95(s, 3/5•3H), 2.20 68.51 6.56 12.78 (s, 2/5•3H), 2.75-2.93(m, 2H), 3.07-3.17(m, 2H), 3.17-3.30(m, 3H), 3.39(m, 1H), 3.53(m, 1H), 3.67(s, 2/5•3H), 3.72(s, 3/5•3H), 4.25-4.61(m, 3H), 6.77-6.87 (m, 2H), 6.87-7.09(m, 4H), 7.12 (m, 1H), 7.14-7.36(m, 4H), 7.55 (d, J=8Hz, 1H), 7.63(t, J=8Hz, 2H), 7.91(d, J=9Hz, 3/5•1H), 8.05(d, J=9Hz, 2/5•1H), 9.92(br s, 0.4H), 9.94(br s, 0.6H), 10.78(br s, 0.6H), 10.80(br s, 0.4H).

Analysis, % Example Mp, Theory/Found No. R ° C. MS ¹H NMR Formula C H N 86 1-(4-i-Pr-piperazinyl) (R) foam 523 (M⁺) ¹H CDCl₃ 0.9-1.1(m, 6H), C₂₉H₃₈ClN₅O₂ 66.46 7.31 13.36 2.05(s, 3H), 2.1-2.5(m, 66.72 7.33 13.30 11H), 2.8-3.1(m, 3H), 3.2(m, 1H), 4.0(m, 1H), 4.5-4.7(m, 2H), 6.9-7.4(m, 9H), 7.63(d, J=6Hz, 1H), 8.23(br s, 1H). 87 1-(4-cyclohexyl- foam 563 (M⁺) ¹H CDCl₃ 1.0-1.4(m, 6H), C₃₂H₄₂ClN₅O₂ 68.13 7.50 12.41 piperazinyl) (R) 1.6(m, 1H), 1.7-1.9(m, 4H), 67.93 7.53 12.43 2.08(s, 3H), 2.1-2.6(m, 9H), 2.8-3.1(m, 4H), 4.0(m, 1H), 4.5-4.7(m, 3H), 7.0-7.4(m, 9H), 7.63(d, J=6Hz, 1H), 8.18(br s, 1H).

Analysis, % Example Mp, Theory/Found No. R ° C. MS ¹H NMR Formula C H N 88 Ph foam 455 (M⁺) CDCl₃ 2.10(s, 3H), 2.81-2.94 C₂₈H₂₉N₃O₃ 73.82 6.42  9.22 (m, 2H), 3.32(dd, J=5, 15 73.86 6.44  9.36 Hz, 1H), 3.66(s, 3H), 4.21 (dd, J=13, 15Hz, 1H), 4.36 (ABq, J=15Hz, Δν=43Hz, 2H), 4.46(m, 1H), 6.61-6.80 (m, 3H), 7.00(d, J=5Hz, 1H), 7.10-7.50(m, 7H), 7.70 (d, J=8Hz, 1H), 7.80(d, J=6 Hz, 1H), 7.87(d, J=6Hz, 2H), 7.96(br s, 1H) 89 Ph(CH₂)₂ (RS) foam 483 (M⁺) CDCl₃ 2.05(s, 3H), 2.45(t, C₃₀H₃₃N₃O₃ 74.51 6.88  8.69 J=9Hz, 2H), 2.72-3.12(m, 74.81 7.06  8.39 5H), 3.71(s, 3H), 4.01(dd, J=12, 14Hz, 1H), 4.33(ABq, J=16Hz, Δν=60Hz, 2H), 4.38(m, 1H), 6.58(d, J=9 Hz, 1H), 6.66-6.81(m, 3H), 6.88(d, J=3Hz, 1H), 7.09- 7.38(m, 9H), 7.68(d, J=7 Hz, 1H), 7.98(br s, 1H) 90 Ph(CH₂)₂ (R) foam 283 (M⁺) ¹H CDCl₃ 2.05(s, 3H), 2.46 C₃₀H₃₃N₃O₃ 74.51 6.88  8.69 (t, J=8Hz, 2H), 2.70-2.90(m, 74.30 6.66  8.46 2H), 2.96(t, J=8Hz, 2H), 3.10(m, 1H), 3.71(s, 3H), 4.03(m, 1H), 4.24(d, J=17 Hz, 1H), 4.33-4.50(m, 2H), 6.60-6.86(m, 4H), 6.89(s, 1H), 7.05-7.40(m, 9H), 7.69 (d, J=8Hz, 1H), 8.03(s, 1H) 91 Ph(CH₂)₂ (S) foam 483 (M⁺) ¹H CDCl₃ 2.04(s, 3H), 2.45 C₃₀H₃₃N₃O₃ 74.51 6.88  8.69 (t, J=8Hz, 2H), 2.73-2.89(m, 74.60 6.96  8.70 2H), 2.96(t, J=8Hz, 2H), 3.06(dd, J=4, 10Hz, 1H), 3.71(s, 3H), 4.03(m, 1H), 4.20-4.50(m, 3H), 6.58-6.88 (m, 4H), 6.89(s, 1H), 7.07- 7.40(m, 9H), 7.69(d, J=8 Hz, 1H), 8.03(s, 1H) 92 PhCH₂O (R) foam 485 (M⁺) ¹H CDCl₃ 2.09(s, 3H), 2.83 C₂₉H₃₁N₃O₄ 71.73 6.43  8.65 (dd, J=7, 15Hz, 1H), 2.95 71.61 6.21  8.67 (dd, J=3, 14Hz, 1H), 3.10 (dd, J=3, 14Hz, 1H), 3.70(s, 3H), 3.96(m, 1H), 4.22(m, 1H), 4.26(m, 1H), 4.72(s, 1H), 5.12(s, 2H), 5.68(m, 1H), 6.68-6.83(m, 2H), 6.97 (m, 1H), 7.07-7.46(m, 10H), 7.66(d, J=8Hz, 1H), 8.02(s, 1H) 93 PhCH₂O (S) oil 485 (M⁺) ¹H CDCl₃ 1.70-2.10(m, 3H), C₂₉H₃₁N₃O₄ 71.73 6.43  8.65 2.75-3.00(m, 2H), 3.10(m, 71.90 6.60  8.51 1H), 3.70(s, 3H), 3.95(m, 1H), 4.10(m, 1H), 4.45(m, 1H), 4.61(s, 1H), 5.13(s, 2H), 5.73(m, 1H), 6.66-6.85 (m, 2H), 6.95(m, 1H), 7.03- 7.50(m, 10H), 7.66(d, J=8 Hz, 1H), 8.02(br s, 1H). 94 Ph(CH₂)₃ foam 497 (M⁺) CDCl₃ 1.88-2.00(m, 2H), C₃₁H₃₅N₃O₃ 74.82 7.09  8.44 2.09(s, 3H), 2.13-2.23(m, 74.58 7.13  8.32 2H), 2.61(t, J=8Hz, 2H), 2.78-2.92(m, 2H), 3.12(dd, J=4, 9Hz, 1H), 3.69(s, 3H), 4.10(dd, J=7, 9Hz, 1H), 4.40 (ABq, J=17Hz, Δν=56Hz, 2H), 4.40(m, 1H), 6.61(br s, 1H), 6.67-6.81(m, 3H), 6.99 (s, 1H), 7.04-7.36(m, 9H), 7.70(d, J=8Hz, 1H), 7.98 (br s, 1H) 95 PhCO(CH₂)₂ (RS) foam 511 (M⁺) CDCl₃ 2.17(s, 3H), 2.57(t, C₃₁H₃₃N₃O₄ 72.78 6.50  8.21 J=7Hz, 2H), 2.79-2.89(m, 72.71 6.38  7.95 2H), 3.11(dd, J=6, 14Hz, 1H), 3.21-3.45(m, 2H), 3.68 (s, 3H), 4.09(dd, J=12, 14 Hz, 1H), 4.38(ABq, J=16Hz, Δν=75Hz, 2H), 4.40(m, 1H), 6.71-6.79(m, 4H), 7.01(d, J=3Hz, 1H), 7.09-7.22(m, 3H), 7.34(d, J=7Hz, 1H), 7.46(t, J=8Hz, 2H), 7.56(m, 1H), 7.70(d, J=8Hz, 1H), 8.00(d, J=8Hz, 3H) 96 PhCO(CH₂)₂ (R) oil 511 (M⁺) ¹H CDCl₃ 2.19(s, 3H), 2.58(t, J= C₃₁H₃₃N₃O₄ 72.78 6.50  8.21 4Hz, 1H), 2.80-2.93(m, 2H), 72.84 6.61  8.22 3.05(m, 1H), 3.20-3.46(m, 3H), 3.70(s, 3H), 4.05(m, 1H), 4.26 (m, 1H), 4.33-4.60(m, 2H), 6.66-6.86(m, 4H), 7.00(s, 1H), 7.06-7.23(m, 3H), 7.30(d, J=8Hz, 1H), 7.43-7.53(m, 2H), 7.58(d, J=8Hz, 1H), 7.70(d, J= 8Hz, 1H), 7.97(d, J=8Hz, 2H), 8.12(s, 1H). 97 PhCO(CH₂)₂ (S) oil 511 (M⁺) ¹H DMSO (4:3 mixture of amide C₃₁H₃₃N₃O₄ 72.78 6.50  8.21 rotamers) 1.70(s, 4/7•1H), 72.86 6.50  8.17 1.77(s, 3/7•1H), 1.92(s, 4/7•3H), 2.00(s, 3/7•3H), 2.40(m, 1H), 2.60-2.80(m, 2H), 3.10-3.25(m, 3H), 3.50(m, 1H), 3.65(s, 3/7•3H), 3.72(s, 4/7•3H), 4.25-4.60(m, 3H), 6.75-7.35(m, 8H), 7.45-7.70 (m, 4H), 7.74(d, J=8Hz, 1H), 7.80-8.00(m, 2H), 10.77(m, 1H). 98 PhCO(CH₂)₃ foam 525 (M⁺) CDCl₃ 2.00-2.11(m, 2H), 2.11 C₃₂H₃₅N₃O₄ 73.12 6.71  7.99 (s, 3H), 2.25(t, J=7Hz, 2H), 72.86 6.66  7.73 2.76-2.91(m, 2H), 2.98-3.16 (m, 3H), 3.71(s, 3H), 4.04(dd, J=11, 13Hz, 1H), 4.38(ABq, J=17Hz, Δν=54Hz, 2H), 4.39(m, 1H), 6.60-6.81(m, 4H), 6.98(s, 1H), 7.08-7.24(m, 3H), 7.34(d, J=9Hz, 1H), 7.45(t, J=9Hz, 2H), 7.55(m, 1H), 7.70 (d, J=9Hz, 1H), 7.96(d, J=8Hz, 2H), 8.01(br s, 1H)

Analysis, % Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 99 H MeCO foam 377 (M⁺) CDCl₃ 1.42(d, J=8Hz, 3H), C₂₃H₂₇N₃O₂ 73.18 7.21 11.13 (RS) 1.92(s, 3H), 2.23(s, 3H), 73.35 7.46 10.90 2.53(dd, J=8, 14Hz, 1H), 2.85-3.05(m, 2H), 3.28(m, 1H), 3.81(dd, J=10, 14Hz, 1H), 4.94(q, J=8Hz, 1H), 6.82(m, 1H), 6.82-7.27(m, 7H), 7.27-7.45(m, 2H), 7.54 (d, J=8Hz, 1H), 8.01(br s, 1H) 100 H MeCO foam 377 (M⁺) CDCl₃ 1.38(d, J=8Hz, 3H), C₂₃H₂₇N₃O₂ 73.18 7.21 11.13 (RR) 1.93(s, 3H), 2.17(s, 3H), 73.39 7.33 10.96 2.68(dd, J=8, 14Hz, 1H), 2.74(dd, J=4, 14Hz, 1H), 3.20(dd, J=4, 14Hz, 1H), 3.91(dd, J=10, 14Hz, 1H), 4.37(m, 1H), 4.92(m, 1H), 6.78-7.27(m Hz, 9H), 7.37 (d, J=8Hz, 1H), 7.75(d, J=8 Hz, 1H), 7.98(br s, 1H) 101 1-(4-(1- H foam 501 (M⁺) CDCl₃ 1.32(d, J=7Hz, 3H), C₃₁H₄₃N₅O 74.21 8.64 13.96 piperidinyl)- 1.15-1.91(m, 11H), 1.91- 74.50 8.49 13.94 piperidinyl) 2.23(m, 3H), 2.30-2.60(m, (RS) 6H), 2.65(dd, J=6, 14Hz, 1H), 2.72-2.94(m, 4H), 3.01 (dd, J=6, 14Hz, 1H), 3.72 (q, J=7Hz, 1H), 4.35(m, 1H), 6.95(d, J=2Hz, 1H), 7.03-7.42(m, 9H), 7.64(d, J=8Hz, 1H), 8.08(br s, 1H) 102 1-(4-(1- H foam 501 (M⁺) DMSOd₆ 1.23(d, J=6Hz, C₃₁H₄₃N₅O 74.21 8.64 13.96 piperidinyl)- 3H), 1.12-1.70(m, 11H), 73.93 8.65 13.89 piperidinyl) 1.89-2.01(m, 2H), 2.01-2.17 (RR) (m, 2H), 2.23-2.43(m, 5H), 2.52(m, 1H), 2.72(m, 1H), 2.75(ABq, J=15Hz, Δν=30 Hz, 2H), 2.83(dd, J=8, 14 Hz, 1H), 2.95(dd, J=6, 14 Hz, 1H), 3.66(q, J=6Hz, 1H), 4.06(m, 1H), 6.95(t, J=8Hz, 1H), 6.99-7.10(m, 2H), 7.10-7.41(m, 6H), 7.49 (d, J=9Hz, 1H), 7.56(d, J=8 Hz, 1H), 10.78(br s, 1H) 103 1-(4-(1- MeCO foam 543 (M⁺) CDCl₃ 1.29-1.88(m, 12H), C₃₃H₄₅N₅O₂ 72.89 8.34 12.88 piperidinyl)- 1.88-2.08(m, 2H), 2.15(s, 73.13 8.27 12.91 piperidinyl) 3H), 2.21(m, 1H), 2.36-2.62 (RS) (m, 6H), 2.62-2.88(m, 4H), 2.96(dd, J=6, 14Hz, 1H), 3.28(dd, J=6, 14Hz, 1H), 3.65(dd, J=10, 14Hz, 1H), 3.82(m, 1H), 4.98(m, 1H), 6.85-7.45(m, 9H), 7.48-7.59 (m, 2H), 8.10(br s, 1H) 104 1-(4-(1- MeCO foam 543 (M⁺) DMSO-d₆ 2:1 mixture of C₃₃H₄₅N₅O₂ 72.89 8.34 12.88 piperidinyl)- amide rotamers 1.19-1.84 72.65 8.14 12.71 piperidinyl) (m, 12H), 1.84-2.16(m, 3H), (RR) 2.06(s, 3H), 2.32-2.52(m, 5H), 2.57-3.00(m, 6H), 3.20 (m, 1H), 3.79(dd, J=11, 14 Hz, 1H), 4.28(m, 1H), 5.04 (m, 2/3•1H), 5.49(m, 1/3•1H), 6.89-7.15(m, 5H), 7.15-7.28(m, 3H), 7.32(d, J=8Hz, 1H), 7.47(m, 1H), 8.41(m, 1H), 10.77 (br s, 1H)

Analysis, Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 105 H 2-OMe foam 351 (M⁺) CDCl₃ 1.97(s, 3H), 2.38(m, 1H), C₂₁H₂₅N₃O₂ 71.77 7.17 11.96 2.73(dd, J=6, 12Hz, 1H), 2.82 71.48 6.90 12.09 (dd, J=6, 12Hz, 1H), 2.97(dd, J=8, 14Hz, 1H), 3.10(dd, J=6, 14Hz, 1H), 3.75-3.94(m, 2H), 3.82(s, 3H), 4.42(m, 1H), 6.34 (br d, J=8Hz, 1H), 6.77-6.95(m, 2H), 7.01(d, J=2Hz, 1H), 7.07- 7.33(m, 4H), 7.37(d, J=8Hz, 1H), 7.68(d, J=8Hz, 1H), 8.13 (br s, 1H) 106 MeCO 2-OMe 147-148 393 (M⁺) CDCl₃/DMSOd₆ 1.95(s, 3H), C₂₃H₂₇N₃O₃ 70.21 6.92 10.68 2.13(s, 3H), 2.81(dd, J=8, 16 69.93 7.06 10.58 Hz, 1H), 2.89(dd, J=4, 14Hz, 1H), 3.72(s, 3H), 3.99(t, J=10 Hz, 1H), 4.35(m, 1H), 4.37 (ABq, J=16Hz, Δν=58Hz, 2H), 7.65-7.82(m, 4H), 6.99(s, 1H), 7.01-7.22(m, 3H), 7.37(d, J=7 Hz, 1H), 7.66(d, J=8Hz, 1H), 9.19(br s, 1H) 107 1-(4-Ph- 2-OMe foam 553 (M⁺) CDCl₃ 1.93(s, 3H), 2.72-2.98 C₃₃H₃₉N₅O₃ 71.58 7.10 12.65 piperazinyl) (m, 6H), 3.08(dd, J=6, 15Hz, 71.33 7.09 12.51 CH₂CO 1H), 3.18-3.52(m, 6H), 3.73 (s, 3H), 4.02(t, J=13Hz, 1H), 4.33(d, J=16Hz, 1H), 4.42 (m, 1H), 4.64(d, J=16Hz, 1H), 6.45(d, J=8Hz, 1H), 6.66- 6.95(m, 6H), 7.00(d, J=3Hz, 1H), 7.04-7.30(m, 5H), 7.36 (d, J=9Hz, 1H), 7.67(d, J=8Hz, 1H), 8.07(br s, 1H) 108 1-(4-(1- H foam 530 CDCl₃ 2:1 mixture of amide C₃₂H₄₃N₅O₂ 72.56 8.18 13.22 piperidinyl)- (M + 1) rotamers 1.24-1.89(m, 10H), 72.29 8.04 13.21 piperidinyl) 1.90(s, 2/3•3H), 1.96(s, CH₂CO 1/3•3H), 1.92-2.10(m, 2H), 2.23(m, 1H), 2.34(m, 1H), 2.42- 2.53(m, 2H), 2.62-2.94(m, 5H), 3.01-3.23(m, 3H), 3.57 (dd, J=12, 14Hz, 1/3•1H), 4.06(dd, J=12, 15Hz, 2/3•1H), 4.43(br s, 2/3•1H), 4.57(ABq, J=16Hz, Δν=169Hz, 2/3•2H), 4.58(ABq, J=16Hz, Δν=273Hz, 1/3•2H), 4.63(br s, 1/3•1H), 6.38(d, J=8Hz, 2/3•1H), 6.73(d, J=8Hz, 1/3•1H), 6.84-6.98 (m, 2H), 7.05-7.30(m, 6H), 7.34(d, J=7Hz, 1H), 7.53(d, J=8Hz, 1/3•1H), 7.66(d, J=8Hz, 2/3•1H), 7.99(br s, 2/3•1H), 8.13(br s, 1/3•1H) 109 1-(4-(1- 2-Cl foam 563 (M⁺) CDCl₃ 3:1 mixture of amide C₃₂H₄₂ClN₅O₂ 68.13 7.50 12.41 piperidinyl)- rotamers 1.38-1.86(m, 11H), 66.92 7.48 12.32 piperidinyl) 1.93(s, 3/4•3H), 1.98(s, CH₂CO 1/4•3H), 1.86-2.12(m, 2H), 2.18-2.73(m, 5H), 2.77-2.98 (m, 3H), 2.99-3.19(m, 3H), 3.57 (dd, J=12, 14Hz, 1/4•1H), 4.10(dd, J=12, 14Hz, 3/4•1H), 4.41(m, 3/4•1H), 4.65(m, 1/4•1H), 4.66(ABq, J=18Hz, Δν=107Hz, 3/4•2H), 4.72(ABq, J=15Hz, Δν=157Hz, 1/4•2H), 6.40(br d, J=7Hz, 1H), 6.90(d, J=7Hz, 1H), 7.02(br s, 1H), 7.06-7.40(m, 6H), 7.55(d, J=8Hz, 1/4•1H), 7.64(d, J=8Hz, 3/4•1H), 8.04(br s, 1H)

Analysis, Example Mp Theory/Found No. ° C. MS ¹H NMR Formula C H N 110 foam 537 (M⁺) ¹H DMSO (3:2 mixture of amide rotomers) 1.79(s, 3/5•3H), 1.81(s, C₃₃H₃₉N₅O₂ 73.71 7.31 13.02 2/5•3H), 2.25-2.46(m, 4H), 2.59-3.21(m, 10H), 3.23-3.67(m, 4H), 4.46 73.64 7.33 13.08 (m, 1H), 6.76(t, J=8Hz, 1H), 6.91(d, J=8Hz, 2H), 6.94-7.40(m, 11H), 7.60(m, 1H), 7.81-8.05(m, 1H), 10.81(br s, 2/5•1H), 10.84(br s, 3/5•1H).

Analysis, Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 111 5-Br H oil 590, 592 CDCl₃ 2.33-2.45(m, 2H), 2.45- C₃₁H₃₆N₅O₂Br 63.05 6.14 11.86 (M + 1) 2.53(m, 2H), 2.80-3.10(m, 63.21 6.21 11.59 for Br 11H), 3.75(s, 1H), 3.88(s, 3H), isotopes) 3.94(d, J=4Hz, 2H), 6.80-6.96 (m, 6H), 7.10(s, 1H), 7.20-7.36 (m, 5H), 7.40(m, 1H), 7.75 (s, 1H), 8.20(s, 1H) 112 5-OCH₂Ph H oil 617 (M⁺) DMSO-d₆ 2.30-2.65(m, 8H), C₃₈H₄₃N₅O₃ 73.88 7.02 11.34 2.80-3.15(m, 8H), 3.31(s, 1H), 74.09 7.03 11.31 3.64(s, 2H), 3.72(s, 3H), 4.15 (m, 1H), 6.65-6.95(m, 6H), 7.05(s, 1H), 7.10-7.25(m, 5H), 7.25-7.40(m, 4H), 7.43(d, J=9Hz, 2H), 7.50(d, J=9Hz, 1H), 10.70(s, 1H) 113 1-Me MeCO oil 567 (M⁺) CDCl₃ 2.11(s, 3H), 2.36-2.60 C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 (m, 3H), 2.85-3.20(m, 10H), 71.69 7.36 12.28 3.71(s, 3H), 3.77(s, 3H), 3.97 (br s, 1H), 4.36-4.60(m, 3H), 6.78-7.00(m, 7H), 7.10(s, 1H), 7.20-7.35(m, 6H), 7.66(d, J=8Hz, 1H) 114 6-Me MeCO oil FD-MS ¹H CDCl₃ 2.10(s, 3H), 2.10(m, C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 567 (M⁺) 1H), 2.40-2.70(m, 7H), 2.90- 71.72 6.99 12.10 3.10(m, 7H), 3.16(dd, J=4, 13Hz, 1H), 3.78(s, 3H), 3.97(m, 1H), 4.40-4.70(m, 3H), 6.80- 7.10(m, 8H), 7.16(s, 1H), 7.20- 7.40(m, 3H), 7.45(m, 1H), 7.54 (d, J=8Hz, 1H), 7.94(m, 1H). 115 7-Me MeCO foam 567 (M⁺) ¹H CDCl₃ 2.08(s, 3H), 2.35- C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 2.53(m, 7H), 2.88-3.15(m, 71.82 7.31 12.32 10H), 3.76(s, 3H), 4.48(ABq, J=17.1Hz, Δν=41.2Hz, 2H), 4.55(m, 1H), 6.78-6.90 (m, 6H), 6.96-7.08(m, 3H), 7.22(m, 3H), 7.40(m, 1H), 7.50 (d, J=8.0Hz, 1H), 7.95(s, 1H). 116 5-Br MeCO 124-126 631, 633 CDCl₃ 2.12(s, 3H), 2.40-2.66 C₃₃H₃₈N₅O₃Br 62.66 6.05 11.07 (M⁺'s for (m, 4H), 2.83-3.20(m, 9H), 3.80 62.92 6.04 11.25 Br (s, 3H), 3.96(m, 1H), 4.43- isotopes) 4.60(m, 3H), 6.83-6.96(m, 6H), 7.10(s, 1H), 7.20-7.33(m, 5H), 7.46(br s, 1H), 7.75(s, 1H), 8.44(s, 1H) 117 5-OMe MeCO oil 583 (M⁺) DMSO-d₆ 1:1 mixture of amide C₃₄H₄₁N₅O₄ Exact Mass rotamers 1.86(s, 1/2•3H), 1.94(s, FAB 1/2•3H), 2.23-2.43(m, 4H), (M + 1) 2.73-2.93(m, 4H), 2.93-3.10(m, theory: 4H), 3.16(m, 1H), 3.56(m, 1H), 584.3237 3.66(s, 1/2•3H), 3.69(s, found: 1/2•3H), 3.71(s, 1/2•3H), 584.3214 3.72(s, 1/2•3H), 4.23-4.60 (m, 3H), 6.66-7.00(m, 7H), 7.08(s, 2H), 7.15-7.26(m, 4H), 7.59(d, J=8Hz, 1/2•1H), 7.77(d, J=8Hz, 1/2•1H), 10.65(s, 1H) 118 5-OCH₂Ph MeCO oil 660 DMSO-d₆ 3:2 mixture of amide C₄₀H₄₅N₅O₄ 72.81 6.87 10.61 (M + 1⁺) rotamers 1.94(s, 3/5•3H), 2.04(s, 72.58 6.85 10.37 2/5•3H), 2.23-2.56(m, 5H), 2.66-2.93(m, 4H), 2.93-3.13 (m, 3H), 3.30-3.50(m, 3H), 3.58(m, 1H), 3.68(s, 2/5•3H), 3.70(s, 3/5•3H), 4.24-4.60 (m, 3H), 6.70-7.00(m, 7H), 7.06(s, 1H), 7.13-7.50(m, 10H), 7.55(d, J=8Hz, 3/5•1H), 7.66(d, J=8Hz, 2/5•1H), 10.70(s, 1H)

Analysis, % Example Mp Theory/Found No. ° C. MS ¹H NMR Formula C H N 119 foam 548 (M⁺) ¹H CDCl₃ 1.30-1.72(m, 10H), 1.96-2.24(m, 6H), 2.41-2.56(m, 5H), C₃₂H₄₂FN₅O₂ 70.17 7.73 12.79 2.70-2.77(m, 1H), 2.85(s, 2H), 2.87-3.00(m, 2H), 3.16(dd, J=4.7, 69.94 7.80 12.74 13.8Hz, 1H), 4.00(dd, J=10.1, 13.8Hz, 1H), 4.48-4.57(m, 1H), 4.55(ABq, J=17.0Hz, Δν=47.7Hz, 2H), 6.93(m, 1H), 7.08-7.16(m, 3H), 7.21-7.41(m, 6H), 8.27(s, 1H).

Analysis, Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 120 5-Br H oil 596, 598 DMSO-d₆ 1.20-1.56(m, 12H), C₃₁H₄₂BrN₅O₂ 62.41 7.10 11.74 (M + 1) 1.75-2.00(m, 2H), 2.20-2.40(m, 62.63 6.96 12.01 for Br 7H), 2.60-2.80(m, 3H), 2.85(d, isotopes) J=6Hz, 2H), 3.63(br s, 2H), 3.74(s, 3H), 4.10(m, 1H), 6.83-6.93(m, 2H), 7.10- 7.23(m, 3H), 7.23-7.30(m, 2H), 7.45(d, J=8Hz, 1H), 7.55(s, 1H), 11.10(s, 1H) 121 5-OMe H oil 547 (M⁺) DMSO-d₆ 1.20-1.70(m, 11H), C₃₂H₄₅N₅O₃ 70.17 8.28 12.79 1.66-2.20(m, 4H), 2.20-2.43(m, 70.29 8.09 12.56 4H), 2.43-2.65(m, 3H), 2.65- 2.90(m, 4H), 3.61(s, 2H), 3.77 (s, 3H), 3.80(s, 3H), 4.13(m, 1H), 6.70(m, 1H), 6.80-7.00 (m, 2H), 7.02(s, 1H), 7.08(s, 1H), 7.10-7.40(m, 3H), 7.45(d, J=8Hz, 1H), 10.65 (s, 1H) 122 5-OCH₂Ph H oil 624 DMSO-d₆ 1.20-1.33(m, 11H), C₃₈H₄₉N₅O₃ 73.16 7.92 11.23 (M + 1⁺) 1.80-2.10(m, 4H), 2.25-2.40(m, 73.45 7.92 11.14 5H), 2.50-2.60(m, 3H), 2.65-2.90(m, 5H), 3.63(s, 2H), 3.74(s, 3H), 4.08(m, 1H), 6.77 (d, J=2Hz, 1H), 6.80-7.00 (m, 2H), 7.03(s, 1H), 7.13- 7.25(m, 3H), 7.25-7.50(m, 7H), 10.70(s, 1H) 123 6-F H foam 536 ¹H CDCl₃ 1.22-1.78(m, 12H), C₃₁H₄₂FN₅O₂ 71.17 8.26 12.21 (M + 1) 1.95-2.15(m, 3H), 2.43-2.57(m, 70.89 8.26 11.91 4H), 2.69-3.08(m, 7H), 3.74-3.88(m, 5H), 4.39(m, 1H), 6.85-7.13(m, 5H), 7.21-7.27(m, 2H), 7.33(d, J=4.9Hz, 1H), 7.58(m, 1H), 8.25(s, 1H). 124 1-Me MeCO oil 573 (M⁺) DMSO-d₆ 3:2 mixture of amide C₃₄H₄₇N₅O₃ 71.17 8.25 12.21 rotamers 1.30-1.60(m, 11H), 71.30 7.97 12.09 1.80-1.95(m, 2H), 1.93(s, 3/5•3H), 2.03(s, 2/5•3H), 2.05(m, 1H), 2.40(br s, 3H), 2.50-2.86(m, 6H), 3.14(m, 1H), 3.67(m, 1H), 3.68(s, 3/5•6H), 3.71(s, 2/5•6H), 4.23-4.56 (m, 3H), 6.79(m, 1H), 6.86-7.28 (m, 5H), 7.34(d, J=8Hz, 1H), 7.53(m, 3/5•2H), 7.63(m, 2/5•2H), 8.30(s, 1H) 125 4-Me MeCO foam 573 (M⁺) ¹H CDCl₃ 1.46(m, 3H), 1.51- C₃₄H₄₇N₅O₃ 71.17 8.26 12.21 1.81(m, 7H), 2.01-2.26(m, 70.84 8.26 11.91 6H), 2.43-2.68(m, 5H), 2.70- 2.84(m, 4H), 2.87(s, 2H), 3.07- 3.24(m, 3H), 3.78(s, 3H), 3.98 (dd, J=9.8, 13.6Hz, 1H), 4.45-4.61(m, 3H), 6.84(m, 3H), 6.88-6.94(m, 1H), 7.03-7.10(m, 2H), 7.15- 7.39(m, 3H), 8.07(s, 1H). 126 5-Me MeCO foam 573 (M⁺) ¹H CDCl₃ 1.25-1.72(m, 11H), C₃₄H₄₇N₅O₃ 71.17 8.26 12.21 1.99-2.17(m, 6H), 2.46(m, 7H), 71.45 8.33 11.96 2.75(dd, J=1.4, 9.7Hz, 1H), 2.86(s, 2H), 2.91(d, J=7.0Hz, 1H), 2.99(d, J=6.3Hz, 1H), 3.14(dd, J=4.7, 13.8Hz, 1H), 3.77(s, 3H), 3.96(dd, J=10.1, 13.8Hz, 1H), 4.49(ABq, J= 17.0Hz, Δν=40.3Hz, 2H), 4.54(m, 1H), 6.82-6.89(m, 3H), 7.02(m, 2H), 7.23(d, H=8.1Hz, 2H), 7.42(m, 2H), 7.95(s, 1H) 127 6-Me MeCO oil 573 (M⁺) ¹H CDCl₃ 1.25-1.40(m, 2H), C₃₄H₄₇N₅O₃ 71.17 8.26 12.21 1.40-1.52(m, 3H), 1.52-1.80 70.99 8.05 12.41 (m, 6H), 2.02(d, J=12Hz, 2H), 2.09(s, 3H), 2.46(s, 3H), 2.46-2.60(m, 5H), 2.75(m, 1H), 2.86(s, 2H), 2.90(d, J= 15Hz, 1H), 2.95(d, J=15Hz, 1H), 3.15(dd, J=9, 18Hz, 1H), 3.70(s, 3H), 3.95(m, 1H), 4.44 (s, 1H), 4.50-4.60(m, 2H), 6.80-6.93(m, 3H), 6.93- 7.00(m, 2H), 7.14(s, 1H), 7.25 (s, 1H), 7.42(d, J=9Hz, 1H), 7.53(d, J=8Hz, 1H), 8.03 (brs, 1H) 128 7-Me MeCO foam 573 (M⁺) ¹H CDCl₃ 1.32-1.41(m, 4H), C₃₄H₄₇N₅O₃ 71.17 8.26 12.21 1.45-1.66(m, 6H), 1.96-2.07 71.33 8.20 12.29 (m, 2H), 2.09(s, 3H), 2.19 (m, 1H), 2.48-2.58(m, 8H), 2.74(m, 1H), 2.81-3.07(m, 4H), 3.14(dd, J=4.6, 13.8Hz, 1H), 3.76(s, 3H), 3.97(dd, J=10.2, 13.8Hz, 1H), 4.47 (ABq, J=17.1Hz, Δν= 42.3Hz, 2H), 4.55(m, 1H), 6.78-6.87(m, 3H), 6.96- 7.07(m, 3H), 7.23(m, 1H), 7.45 (d, J=8.6Hz, 1H), 7.51(d, J=7.6Hz, 1H), 8.18(s, 1H). 129 5-Br MeCO oil 638, 640 DMSO-d₆ 2:1 mixture of amide C₃₃H₄₄BrN₅O₃ (M + 1⁺'s rotamers 1.20-1.60(m, 3H), for Br 1.60-1.90(m, 6H), 1.95(s, isotopes) 2/3•3H), 2.07(s, 1/3•3H), Exact 1.90-2.07(m, 3H), 2.55-2.90 Mass FAB (m, 5H), 2.90-3.20(m, 4H), (M + 1): 3.20-3.50(m, 3H), 3.62(m, 1H), theory 3.73(s, 3H), 4.20-4.42(m, 638.2706 3H), 6.85(m, 1H), 6.90-7.00 found: (m, 2H), 7.10-7.30(m, 4H), 638.2729 7.50(m, 1H), 7.70(s, 2/3•1H), 7.75(s, 1/3•1H), 11.10(s, 1H) 130 5-OMe MeCO oil 590 DMSO-d₆ 3:2 mixture of amide C₃₄H₄₇N₅O₄ 69.24 8.03 11.87 (M + 1⁺) rotamers 1.20-1.60(m, 12H), 69.52 8.14 11.92 1.73-1.96(m, 2H), 1.93(s, 3/5•3H), 2.02(s, 2/5•3H), 2.33-2.43(m, 4H), 2.60-2.90 (m, 6H), 3.57(m, 1H), 3.70(s, 3H), 3.71(s, 3H), 4.26-4.56 (m, 3H), 6.66(d, J=6Hz, 1H), 6.82(m, 1H), 6.93(m, 2H), 7.03 (s, 2H), 7.20(m, 2H), 7.44(d, J=6Hz, 3/5•1H), 7.68(d, J=6Hz, 2/5•1H), 10.65 (s, 1H) 131 5-OCH₂Ph MeCO oil 666 DMSO-d₆ 1.16-1.80(m, 12H), C₄₀H₅₁N₅O₄ 72.15 7.72 10.52 (M + 1⁺) 1.90(m, 6H), 2.20-2.43(m, 3H), 71.95 7.66 10.31 2.53-2.90(m, 6H), 3.16(m, 1H), 3.43(m, 1H), 3.60(m, 1H), 3.70 (d, J=6Hz, 3H), 4.20-4.60 (m, 3H), 6.73-6.88(m, 3H), 6.88-7.00(m, 2H), 7.04(s, 1H), 7.15-7.26(m, 3H), 7.26-7.40(m, 3H), 7.40- 7.53(m, 2H), 10.70(s, 1H) 131a 6-F MeCO foam 577 (M⁺) CDCl₃ δ 1.32-1.46(m, 4H), C₃₃H₄₄FN₅O₃ 68.61 7.68 12.12 1.58-1.66(m, 6H), 1.97- 68.76 7.86 12.28 2.08(m, 2H), 2.11(s, 3H), 2.19(m, 1H), 2.49(m, 5H), 2.72-3.04(m, 5H), 3.13(dd, J=4.5Hz, Δν=13.9Hz, 1H), 3.76(s, 3H), 3.97(dd, J=10.3Hz, Δν=13.7Hz, 1H), 4.47(ABq, J=17.0Hz, Δν=42.7Hz, 2H), 4.49(m, 1H), 6.78-6.90(m, 1H), 7.00(s, 1H), 7.04(d, 2.2Hz, 1H), 7.23(m, 1H), 7.47(d, J=8.5Hz, 1H), 7.57(dd, J=5.3Hz, Δν= 8.7Hz, 1H), 8.62(s, 1H)

Analysis, % Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 132 1-(4-(1-piperidinyl)- foam 574 ¹H CDCl₃ 1.44(s, 3H), 1.40- C₃₄H₄₇N₅O₃ 71.17 8.26 12.21 piperidinyl) (M + 1⁺) 2.00(m, 13H), 2.08(s, 3H), 70.94 8.38 12.28 2.20-2.40(m, 2H), 2.45-2.80 (m, 6H), 3.16-3.35(m, 2H), 3.66(d, J=14Hz, 1H), 3.81(s, 3H), 4.23(d, J=14Hz, 1H), 4.60 (ABq, J=14Hz, Δν=28Hz, 2H), 6.86(d, J=8Hz, 1H), 6.96 (d, J=8Hz, 1H), 7.03-7.20 (m, 4H), 7.27(s, 2H), 7.40(d, J=8Hz, 1H), 7.60(d, J=6Hz, 2H) 133 1-(4-phenyl)- foam 568 ¹H CDCl₃ 1.56(s, 3H), 2.09(s, C₃₄H₄₁N₅O₃ 71.93 7.28 12.34 piperazinyl (M + 1⁺) 3H), 2.43-2.85(m, 3H), 2.85- 71.68 7.49 12.29 3.20(m, 7H), 3.20-3.50(m, 3H), 3.81(s, 3H), 4.20(d, J=14Hz, 1H), 4.60(ABq, J=18Hz, Δν=56Hz, 2H), 6.80-7.00(m, 6H), 7.00-7.20(m, 3H), 7.20- 7.36(m, 5H), 7.59(d, J=7Hz, 1H), 8.24(s, 1H).

Analysis, % Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 134 Br foam 543, 545 ¹H CDCl₃ 1.31(s, 12H), 3.07 C₂₇H₃₄BrN₃O₄ 59.56 6.29  7.72 (M⁺'s (d, J=14Hz, 1H), 3.25(d, 58.80 6.21  7.47 for Br J=14Hz, 1H), 3.40(d, J=14Hz, isotopes) 1H), 3.66(s, 3H), 3.68(d, J= 14Hz, 1H), 3.80-3.95(m, 2H), 4.23(d, J=16Hz, 1H), 4.64(d, J=16Hz, 1H), 6.82(d, J=8Hz, 1H), 6.90(m, 1H), 7.00-7.15(m, 2H), 7.15-7.30(m, 3H), 7.30- 7.40(m, 2H), 7.55(d, J=8Hz, 1H), 8.07(brs, 1H).

Analysis, % Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 135 1-naphthyl-CH₂ H foam 523 CDCl₃ 2.32-2.45(m, 2H), 2.40 C₃₃H₃₈N₄O₂ 75.83 7.33 10.72 (M + 1⁺) (m, 1H), 2.45-2.57(m, 2H), 75.55 7.26 10.60 2.75-3.10(m, 8H), 3.36(m, 2H), 3.84(s, 3H), 3.92(ABq, J=12 Hz, Δν=22Hz, 2H), 4.48(m, 1H), 6.75-7.00(m, 5H), 7.15- 7.42(m, 6H), 7.42-7.64(m, 3H), 7.74(d, J=8Hz, 1H), 7.83(d, J=8Hz, 1H), 8.28(d, J=8Hz, 1H) 136 2-naphthyl-CH₂ H foam 522 (M⁺) CDCl₃ 2.03(m, 1H), 2.26-2.35 C₃₃H₃₈N₄O₂ 75.83 7.33 10.72 (m, 2H), 2.35-2.55(m, 2H), 76.07 7.25 10.66 2.65-2.95(m, 7H), 2.95- 3.10(m, 2H), 3.18(dd, J=8, 14Hz, 1H), 3.74-4.03(m, 2H), 3.85(s, 3H), 4.45(m, 1H), 6.75 (d, J=9Hz, 2H), 6.78-6.97 (m, 3H), 7.03-7.40(m, 6H), 7.40-7.52(m, 2H), 7.63(s, 1H), 7.66-7.83(m, 3H) 137 3-indolinyl-CH₂ H foam 514 DMSO-d₆ 1:1 mixture of C₃₁H₃₉N₅O₂ 72.48 7.65 13.63 (M + 1⁺) diastereomers 1.54-1.70(m, 72.57 7.50 13.70 1H), 1.86-1.98(m, 1H), 2.52- 2.64(m, 6H), 2.84-3.18(m, 8H) 3.32(br s, 1H), 3.54(m, 1H), 3.64-3.70(m, 2H), 3.76(s, 1/2•3H), 3.78(s, 1/2•3H), 4.03 (m, 1H), 5.40(br s, 1H), 6.44- 6.56(m, 2H), 6.77(t, J=7Hz, 1H), 6.82-6.98(m, 6H), 7.10- 7.24(m, 3H), 7.30(br d, J=8 Hz, 1H), 7.65(t, J=9Hz, 1H) 138 Ph MeCO oil 500 (M⁺) CDCl₃ 2.14(s, 3H), 2.60-2.80 C₃₀H₃₆N₄O₃ 71.97 7.25 11.19 (m, 4H), 3.00-3.20(m, 2H), 71.67 7.29 11.18 3.20-3.43(m, 5H), 3.82(s, 3H), 4.30(m, 1H), 4.40-4.63(m, 2H), 5.18(m, 1H), 6.80-7.06(m, 6H), 7.03-7.40(m, 8H), 8.24(br s, 1H) 139 3,4-diCl Ph MeCO oil 568 (M⁺) ¹H CDCl₃ 2.19(s, 3H), 2.63- C₃₀H₃₄Cl₂N₄O₃ 63.27 6.02  9.84 2.83(m, 2H), 2.93-3.20(m, 4H), 63.12 5.82  9.55 3.20-3.50(m, 3H), 3.50-3.70 (m, 2H), 3.85(s, 3H), 4.23(m, 1H), 4.30-4.60(m, 2H), 5.00 (m, 1H), 6.85-7.06(m, 5H), 7.13(m, 1H), 7.20-7.45(m, 6H), 8.41(br s, 1H). 140 PhCH₂ MeCO oil 514 (M⁺) DMSO-d₆ 3:2 mixture of amide C₃₁H₃₈N₄O₃ 72.35 7.44 10.89 rotamers 1.93(s, 3/5•3H), 72.57 7.47 10.69 2.09(s, 2/5•3H), 2.23- 2.46(m, 4H), 2.60-2.90(m, 4H), 3.00-3.20(m, 2H), 3.30-3.53(m, 4H), 3.75(s, 3H), 4.20-4.60(m, 3H), 6.70-7.04(m, 7H), 7.04- 7.30(m, 7H), 7.57(d, J=9Hz, 3/5•1H), 7.71(d, J=9Hz, 2/5•1H) 141 1-naphthyl-CH₂ MeCO foam 564 (M⁺) CDCl₃ 2.13(s, 3H), 2.38-2.70 C₃₅H₄₀N₄O₃ 74.44 7.14  9.92 (m, 4H), 2.82-3.07(m, 4H), 74.50 7.25  9.94 3.07-3.30(m, 4H), 3.56(dd, J=7, 14Hz, 1H), 3.66(s, 3H), 4.14(m, 1H), 4.34(ABq, J= 16Hz, Δν=58Hz, 2H), 4.47(m, 1H), 6.52-6.67(m, 2H), 6.73(d, J=8Hz, 1H), 6.77-7.00(m, 3H), 7.09- 7.20(m, 1H), 7.20-7.40(m, 4H), 7.43-7.70(m, 3H), 7.73(d, J=8Hz, 1H), 7.86(d, J=8Hz, 1H), 8.34(d, J=8Hz, 1H) 142 2-naphthyl-CH₂ MeCO foam 564 (M⁺) CDCl₃ 2.12(s, 3H), 2.26-2.50 C₃₅H₄₀N₄O₃ 74.44 7.14  9.92 (m, 4H), 2.59-3.30(m, 9H), 74.46 7.31  9.94 3.78(s, 3H), 3.98(m, 1H), 4.51(ABq, J=17Hz, Δν=30Hz, 2H), 4.53(m, 1H), 6.55-7.03(m, 6H), 7.05-7.39(m, 5H), 7.39- 7.53(m, 2H), 7.60(m, 1H), 7.71-7.85(m, 3H) 143 3- MeCO foam 571 ¹H CDCl₃ 2.15(s, 3H), 2.44- C₃₃H₃₈N₄O₃S 69.45 6.71  9.82 benzo[b]thienyl- (M + 1⁺) 2.60(m, 4H), 2.89-3.26(m, 9H), 69.23 6.71  9.77 CH₂ 3.73(s, 3H), 4.07(dd, J=10.4, 13.9Hz, 1H), 4.43(ABq, J= 16.5Hz, Δν=45.4Hz, 2H), 4.50(m, 1H), 6.74-6.92 (m, 6H), 7.15(s, 1H), 7.18-7.30 (m, 3H), 7.39(m, 2H), 7.57(d, J=8.1Hz, 1H), 7.87(d, J=7.4Hz, 1H), 7.98(d, J=7.6Hz, 1H). 144 3-indolinyl-CH₂ MeCO 102-105 556 CDCl₃ 1:1 mixture of C₃₃H₄₁N₅O₃ (M + 1⁺) diastereomers 1.57-2.08(m, 2H), Exact Mass 2.15(s, 1/2•3H), 2.17(s, FAB 1/2•3H), 2.75-3.60(m, (M + 1): 13H), 3.65-4.00(m, 2H), 3.82(s, calc.: 1/2•3H), 3.85(s, 1/2•3H), 556.3287 4.18-4.48(m, 2H), 4.58(s, 2H), found: 6.70-7.40(m, 13H), 7.67(m, 1H) 556.3280 145 N-Ac-3- MeCO 80-84 597 (M⁺) CDCl₃ 1:1 mixture of C₃₅H₄₃N₅O₄ indolinyl-CH₂ Exact Mass diastereomers 1.70-2.00(m, 2H), FAB 2.13(s, 1/2•3H), 2.17(s, (M + 1): 1/2•3H), 2.23(s, 1/2•3H), calc.: 2.27(s, 1/2•3H), 2.57-3.53 598.3393 (m, 12H), 3.63-4.03(m, 2H), found: 3.82(s, 1/2•3H), 3.85(s, 1/2•3H), 598.3397 4.03-4.33(m, 2H), 4.52(s, 1/2•1H), 4.54(s, 1/2•1H), 6.80-7.40(m, 12H), 7.57(m, 1H), 8.19(m, 1H)

Analysis, % Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 146 Ph oil 506 (M⁺) DMSO-d₆ 2:1 mixture of amide C₃₀H₄₂N₄O₃ 71.11 8.35 11.06 rotamers 1.30-1.76(m, 11H), 71.38 8.25 11.07 1.90-2.20(m, 4H), 1.96(s, 2/3•3H), 2.00(s, 1/3•3H), 2.35-2.55(m, 4H), 2.60-2.95 (m, 4H), 3.78(s, 3H), 4.43(s, 2/3•2H), 4.43(ABq, J=15Hz, Δν=49Hz, 1/3•2H), 4.96(m, 2/3•1H), 5.24(m, 1/3•1H), 6.80-7.05(m, 3H), 7.15-7.40(m, 6H), 8.26(d, J=9Hz, 1H) 147 3,4-diCl—Ph oil FD ¹H CDCl₃ 1.40-1.60(m, 2H), C₃₀H₄₀Cl₂N₄O₃ 62.60 7.01  9.73 574 (M⁺) 1.60-1.80(m, 4H), 1.80-2.05 63.05 6.91  9.78 FAB (m, 5H), 2.17(s, 3H), 2.18(m, Exact Mass 1H), 2.40-2.80(m, 5H), Theory: 2.80-3.05(m, 5H), 3.85(s, 575.2555 3H), 4.23(ABq, J=11Hz, Found: Δν=14Hz, 1H), 4.48 575.2595 (ABq, J=17Hz, Δν=33Hz, (M + 1⁺) 2H), 4.93(m, 1H), 6.85-7.10(m, 4H), 7.20-7.40(m, 3H), 8.35(m, 1H) 148 PhCH₂ oil 520 (M⁺) DMSO 3:2 mixture of amide C₃₁H₄₄N₄O₃ 71.51 8.52 10.76 rotamers 1.30-1.63(m10H), 71.50 8.25 10.51 1.73-2.00(m, 3H), 1.88(s, 3/5•3H), 2.07(s, 2/5•3H), 2.40(m, 3H), 2.55-2.80(m, 4H), 3.15-3.50(m, 5H), 3.76(s, 3H), 4.20-4.60(m, 3H), 6.80-7.00 (m, 3H), 7.05-7.30(m, 6H), 7.49(d, J=9Hz, 3/5•1H), 7.62(d, J=9Hz, 2/5•1H) 149 3-benzo[b]thienyl-CH₂ foam 576 (M⁺) ¹H CDCl₃ 1.41-1.73(m, C₃₃H₄₄N₄O₃S 68.72 7.69  9.71 9H), 2.00-2.21(m, 7H), 2.41- 68.47 7.79  9.77 2.48(m, 4H), 2.59(d, J= 11.4Hz, 1H), 2.74(d, J= 12.6Hz, 1H), 2.88(s, 3H), 3.04(dd, J=4.3, 13.9Hz, 1H), 3.20(dd, J=6.1, 14.5Hz, 1H), 3.70(s, 3H), 4.04(dd, J=10.5, 13.9Hz, 1H), 4.40(ABq, J=16.5Hz, Δν= 46.1Hz, 2H), 4.50(m, 1H), 6.73(m, 2H), 6.78(d, J=8.2Hz, 1H), 7.13(s, 1H), 7.19(m, 1H), 7.27(m, 2H), 7.57(d, J=8.1Hz, 1H), 7.84(d, J=7.5Hz, 1H), 7.96(d, J=7.6Hz, 1H)

Analysis % Example Mp Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 150 H H 144-145 391 (M⁺) CDCl₃ 2.18-2.42(m, 2H), 2.42- C₂₃H₂₉N₅O 70.56 7.47 17.89 2.77(m, 4H), 2.77-3.50(m, 70.51 7.60 17.91 10H), 4.43(m, 1H), 6.73-7.00 (m, 3H), 7.07-7.59(m, 7H), 7.64(d, J=8Hz, 1H), 8.24 (br s, 1H) 151 t-Bu- H 121-122 491 (M⁺) CDCl₃ 1.63(s, 9H), 2.22-2.67 C₂₈H₃₇N₅O₃ 68.40 7.59 14.25 O(CO) (m, 4H), 2.75-3.23(m, 8H), 68.16 7.56 14.05 3.30(m, 1H), 3.40(m, 1H), 4.41(m, 1H), 5.03(m, 1H), 6.75-7.00(m, 4H), 7.07- 7.70(m, 6H), 7.65(d, J=8Hz, 1H), 8.18(br s, 1H) 152 PhCO H 188-189 495 (M⁺) CDCl₃/DMSOd₆ 1.90-2.74 C₃₀H₃₃N₅O₂ 72.70 6.71 14.13 (m, 6H), 2.74-3.40(m, 4H), 72.46 6.71 13.84 3.11(d, J=7Hz, 2H), 3.58- 3.82(m, 2H), 4.55(m, 1H), 6.63-6.96(m, 3H), 7.00- 7.53(m, 10H), 7.68(d, J=8Hz, 1H), 7.60-8.00(m, 3H), 9.28 (br s, 1H) 153 H (c-hexyl)CH₂ foam 487 (M⁺) CDCl₃ 0.73-1.41(m, 6H), C₃₀H₄₁N₅O 73.88 8.47 14.36 1.41-2.08(m, 8H), 2.10-3.38 73.60 8.36 14.24 (m, 14H), 4.56(m, 1H), 6.81(d, J=8Hz, 1H), 6.81-6.97(m, 4H), 7.02-7.40(m, 4H), 7.57-7.73 (m, 2H), 8.10(br s, 1H) Analysis, % Example Purifi- Yield Mp Theory/Found No. R R′ cation % ° C. MS ¹H NMR Formula C H N 154 t-Bu- (c-hexyl)CH₂ chrom 84 mg foam 644 CDCl₃ 0.75-1.00(m, 2H), 1.00- C₃₇H₅₂N₆O₄ 68.92 8.13 13.03 O(CO)NH— (EtOH/ 43% (M⁺) 1.94(m, 10H), 1.44(s, 9H), 68.93 8.28 13.11 CH₂CO EtOAc) 2.40-2.65(m, 3H), 2.65- 3.66(m, 11H), 3.76-4.20(m, 3H), 4.60(m, 1H), 5.54(m, 1H), 6.75-7.05(m, 3H), 7.05- 7.46(m, 7H), 7.67(d, J=8Hz, 1H), 8.13(br s, 1H)

Analysis, % Example Mp Theory/Found No. R ° C. MS ¹H NMR Formula C H N 155 1-(4-(1-piperidinyl)- foam 515 (M⁺) CDCl₃ 1.3-2.1(m, 11H), 2.30 C₃₁H₄₁N₅O₂ 72.20 8.01 13.58 piperidinyl (m, 1H), 2.4-3.3(m, 12H), 72.12 8.22 13.82 3.00(s, 3H), 4.28(m, 1H), 4.74(m, 1H), 7.1-7.5(m, 10H), 7.68(d, J=8Hz, 1H), 8.83(br s, 1H) 156 1-(4-AcNH-4-Ph- 168-9 565 (M⁺) CDCl₃ 1.97(s, 3H), 2.0-2.6 C₃₄H₃₉N₅O₃ 72.19 6.95 12.38 piperidinyl) (m, 8H), 2.8-3.3(m, 4H), 72.47 7.08 12.63 2.99(s, 3H), 3.52(m, 1H), 4.30(m, 1H), 4.72(m, 1H), 5.48(m, 1H), 7.0-7.7(m, 15H), 7.68(m, 1H), 8.41 (br s, 1H) 157 1-(4-Ph-piperazinyl) foam 509 (M⁺) CDCl₃ 2.3-2.7(m, 3H), 2.7-3.7 C₃₁H₃₅N₅O₂ 73.06 6.92 13.74 (m, 10H), 3.02(s, 3H), 4.30(m, 72.91 6.96 13.70 1H), 4.78(m, 1H), 6.7-6.9 (m, 3H), 7.1-7.5(m, 12H), 7.70(d, J=7Hz, 1H), 8.22(br s, 1H) 158 1-(4-cyclohexyl- foam 515 (M⁺) CDCl₃ 1.0-1.3(m, 6H), 1.6-2.0 C₃₁H₄₁N₅O₂ 72.40 8.00 13.66 piperazinyl) (m, 4H), 2.2-2.6(m, 9H), 72.20 8.01 13.58 2.9-3.2(m, 5H), 2.99(s, 3H), 4.38(m, 1H), 4.75(m, 1H), 7.1-7.5(m, 10H), 7.69(d, J=6Hz, 1H), 8.23(br s, 1H)

Analysis, % Example Mp, Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 159 PhCH₂ H oil 312 (M⁺) CDCl₃ 3:1 mixture of amide C₁₉H₂₄N₂O₂ 73.05 7.74  8.97 rotamers 1.90-2.15(m, 2H), 72.82 7.68  8.80 2.17(s, 3/4•3H), 2.23(s, 1/4•3H), 2.62(dd, J=8, 13Hz, 1H), 2.83(dd, J=5, 13Hz, 1H), 3.26-3.55(m, 3H), 3.84(s, 3H), 4.55(d, J=14Hz, 3/4•2H), 4.63(d, J=11Hz, 1/4•2H), 6.80- 7.03(m, 3H), 7.13-7.36(m, 6H) 160 1-Me-3-indolyl- H oil 365 (M⁺) CDCl₃ 2.00-2.30(m, 4H), 2.78 C₂₂H₂₇N₃O₂ 72.30 7.45 11.50 CH₂ (dd, J=7, 15Hz, 1H), 2.93(m, 72.02 7.43 11.24 1H), 3.30-3.60(m, 4H), 3.75(s, 3H), 3.82(s, 3H), 4.60(ABq, J=16Hz, Δν=30, 2H), 6.83-7.00(m, 4H), 7.10(m, 1H), 7.16-7.33(m, 3H), 7.55 (m, 1H) 161 Ph BrCH₂CO oil 418, 420 CDCl₃ 2.22(s, 3H), 3.06(dd, C₂₀H₂₃BrN₂O₃ 57.29 5.53  6.68 (M⁺'s for J=3, 14Hz, 1H), 3.83(s, 2H), 57.24 5.48  6.49 Br 3.87(s, 3H), 4.26(dd, J=11, isotopes) 15Hz, 1H), 4.45(ABq, J= 17Hz, Δν=62Hz, 2H), 4.93(m, 1H), 6.88-7.06(m, 3H), 7.23-7.36(m, 6H), 8.23(d, J=6Hz, 1H) 161a PhCH₂ BrCH₂CO oil 432, 434 CDCl₃ 2.17(s, 3H), 2.66(dd, C₂₁H₂₅BrN₂O₃ 58.21 5.81  6.46 (M⁺'s for J=8, 14Hz, 1H), 2.84(dd, 58.28 5.80  6.32 Br J=9, 14Hz, 1H), 2.97(dd, J=5, isotopes) 14Hz, 1H), 3.73-3.85(m, 5H), 4.05(m, 1H), 4.18(m, 1H), 4.40(ABq, J=16Hz, Δν=39Hz, 2H), 6.79-6.90(m, 3H), 7.16-7.40(m, 7H) 162 1-Me-3- BrCH₂CO foam 485, 487 ¹H CDCl₃ 2.15(s, 3H), 2.90(dd, C₂₄H₂₈BrN₃O₃ 59.26 5.80  8.64 indolylCH₂ (M⁺'s for J=8, 14Hz, 1H), 2.92(dd, J=6, 59.50 5.76  8.52 Br 14Hz, 1H), 3.10(dd, J=4, isotopes), 14Hz, 1H), 3.72(s, 3H), 3.74(s, 3H), 3.80(s, 2H), 4.07(m, 1H), 4.23-4.40(m, 2H), 4.46(m, 1H), 6.70-6.90(m, 4H), 7.13(d, J=8Hz, 1H), 7.20-7.33(m, 3H), 7.33(d, J=12Hz, 1H), 7.68(d, J=8Hz, 1H).

Analysis, % Example Mp, Theory/Found No. ° C. MS ¹H NMR Formula C H N 163 203-205 358 (M⁺) CDCl₃ 2.89(dd, J=9, 14Hz, 1H), 3.19(dd, J=6, 14Hz, 1H), 3.54(dt, J=4, C₂₃H₂₂N₂O₂ 77.07 6.19  7.81 14Hz, 1H), 3.75(m, 1H), 4.54(m, 1H), 7.01(m, 1H), 7.15(m, 1H), 7.18- 76.83 6.21  7.88 7.35(m, 4H), 7.35-7.55(m, 7H), 8.65-8.79(m, 4H)

Analysis, % Example Mp, Theory/Found No. R ° C. MS ¹H NMR Formula C H N 164 Me 183-184 488 CDCl₃ 1.56(s, 3H), 1.90(m, 1H), C₃₃H₃₃N₃O 81.28 6.82  8.62 (M + 1⁺) 2.10(m, 1H), 2.35(m, 1H), 81.26 6.91  8.71 2.5-2.6(br s, 3H), 2.75(m, 1H), 2.95(m, 1H), 3.20(m, 1H), 6.9-7.1(m, 2H), 7.1-7.6 (m, 17H), 7.85(m, 1H), 7.96 (br s, 1H) 165 n-Bu foam 530 ¹H CDCl₃ 0.51-0.81(m, 3H), C₃₆H₃₉N₃O 81.63 7.42  7.93 (M + 1⁺) 0.85-1.31(m, 3H), 1.58(s, 1H), 81.90 7.44  8.03 1.88(s, 2H), 1.98(s, 1H), 2.00-2.10(m, 1H), 2.40-2.78 (m, 3H), 2.86-3.00(m, 2H), 3.20-3.40(m, 2H), 6.88(s, 1H), 6.89-7.08(m, 2H), 7.09-7.38 (m, 11H), 7.40-7.60(m, 5H), 7.80-8.00(m, 2H). 166 n-Hex foam 558 ¹H CDCl₃ 0.80-0.88(m, 6H), C₃₈H₄₃N₃O 81.83 7.77  7.53 (M + 1⁺) 0.88-1.30(m, 7H), 1.92(s, 2H), 82.10 7.74  7.24 1.98(s, 1H), 2.20-2.72(m, 3H), 2.85-3.02(m, 1H), 3.06-3.38(m, 2H), 6.92(s, 1H), 6.97-7.06(m, 2H), 7.11-7.38(m, 12H), 7.38- 7.58(m, 5H), 7.85-7.98(m, 1H) 167 Ph 182-183 550 ¹H DMSO 1.64(s, 3H), 2.55 C₃₈H₃₅N₃O 83.03 6.42  7.64 (M + 1⁺) (m, 1H), 2.59-2.82(m, 3H), 3.30 82.80 6.65  7.39 (m, 1H), 3.63(dd, J=7, 14Hz, 1H), 6.72(d, J=2Hz, 1H), 6.74-6.82(m, 2H), 6.84 (t, J=8Hz, 1H), 6.99(t, J= 8Hz, 1H), 7.05-7.21(m, 10H), 7.21-7.64(m, 10H), 10.67 (br s, 1H). 168 PhCH₂CH₂ 174-175 577 (M⁺) ¹H DMSO (3:2 mixture of amide C₄₀H₃₉N₃O 83.15 6.80  7.27 rotamers) 1.77(s, 3/5•3H), 1.97 82.92 6.83  7.57 (s, 2/5•3H), 2.06-2.44(m, 4H), 2.64-3.04(m, 4H), 3.18 (m, 1H), 3.38-3.61(m, 1H), 6.61-6.71(m, 2H), 6.88(m, 1H), 6.96-7.08(m, 2H), 7.08-7.34 (m, 14H), 7.41-7.56(m, 6H), 10.78(br s, 1H).

Analysis, % Example Mp, Theory/Found No. R R′ R″ ° C. MS ¹H NMR Formula C H N 169 6-Me H 2-OMe oil 566 CDCl₃ 1.90(m, 1H), 2.18-2.33 C₃₉H₃₉N₃O 82.80 6.95  7.43 (M + 1⁺) (m, 2H), 2.44(s, 3H), 2.60(m, 82.81 7.02  7.32 1H), 2.68-2.96(m, 2H), 3.48-3.68(m, 3H), 3.80(s, 3H), 6.86(d, J=8Hz, 3H), 6.99-7.46(m, 15H), 7.46- 7.73(m, 5H), 7.76(s, 1H) 170 H MeCO 2-Cl foam 598 CDCl₃ 3:2 mixture of amide C₃₉H₃₆ClN₃O 78.37 6.07  7.02 (M + 1) rotamers 1.80(s, 3/5•3H), 2.05(s, 78.10 6.25  6.78 2/5•3H), 2.30-2.53(m, 2H), 2.65(m, 1H), 3.00-3.33 (m, 3H), 3.91(ABq, J=20Hz, Δν=30Hz, 3/5•2H), 4.61(ABq, J=18Hz, Δν= 77Hz, 2/5•2H), 6.58-6.67 (m, 3/5•1H), 6.80-6.89(m, 2/5•1H), 6.94-7.33(m, 18H), 7.42-7.56(m, 5H), 7.86 (br s, 1H) 171 6-Me MeCO 2-OMe oil 608 CDCl₃ 3:1 mixture of amide C₄₁H₄₁N₃O₂ 81.02 6.80  6.91 (M + 1⁺) rotamers 1.92(s, 3/4•3H), 1.97(s, 80.90 6.66  7.16 1/4•3H), 2.44(s, 3H), 2.56- 2.76(m, 2H), 3.04-3.36(m, 4H), 3.62(s, 1H), 3.72(s, 3H), 4.03 (d, J=18Hz, 1H), 6.43(d, J=9Hz, 1H), 6.58-7.00(m, 4H), 7.00-7.28(m, 11H), 7.40-7.60(m, 7H), 7.74 (br s, 1H)

Analysis, % Example Mp, Theory/Found No. R ° C. MS ¹H NMR Formula C H N 172 3,4-diCl—Ph oil 447 ¹H CDCl₃ 1.50-1.95(m, 2H), C₂₇H₂₄Cl₂N₂ 72.48 5.41  6.26 (M + 1⁺) 2.04(dd, J=6, 13Hz, 1H), 2.52 72.45 5.38  6.02 (dd, J=4, 12Hz, 1H), 2.90 (m, 1H), 3.67(m, 1H), 7.03(m, 1H), 7.06-7.36(m, 12H), 7.40-7.55(m, 5H).

Analysis, % Example Mp, Theory/Found No. R R′ ° C. MS ¹H NMR Formula C H N 173 Ph H oil 499 CDCl₃ 2.25-2.36(m, 2H), 3.06 C₃₅H₃₄N₂O 84.30 6.87  5.62 (M + 1⁺) (m, 1H), 3.40-3.50(m, 2H), 84.47 6.87  5.74 3.54(s, 3H), 3.75-3.90(m, 2H), 6.74(d, J=8Hz, 1H), 6.85(m, 1H), 6.98(m, 1H), 7.03-7.40(m, 15H), 7.45- 7.60(m, 6H) 174 PhCH₂ H oil 513 CDCl₃ 1.93-2.10(m, 2H), 2.20 C₃₆H₃₆N₂O 84.34 7.08  5.46 (M + 1⁺) (m, 1H), 2.23-2.40(m, 2H), 84.41 6.95  5.76 2.60(m, 1H), 2.75(m, 1H), 3.55- 3.65(m, 2H), 3.82(s, 3H), 6.83- 6.98(m, 4H), 7.03-7.40(m, 14H), 7.53-7.66(m, 6H) 175 Ph MeCO foam 540 (M⁺) CDCl₃ 2:1 mixture of amide C₃₇H₃₆N₂O₂ 82.19 6.71  5.18 rotamers 1.9(s, 2/3•3H), 82.37 6.69  5.03 1.96(s, 1/3•3H), 2.93(m, 1H), 3.05(m, 1H), 3.67(s, 2/3•3H), 3.75(s, 1/3•3H), 3.75(m, 1H), 3.93(d, J=18Hz, 2H), 4.21(ABq J=14Hz, Δν=21Hz, 1H), 6.66- 6.90(m, 3H), 6.90-7.35(m, 15H), 7.35-7.55(m, 6H) 176 3,4-diCl—Ph MeCO 181-182.5 608 (M⁺ ¹H CDCl₃ 1.99(s, 3H), 2.96(dd, C₃₇H₃₄Cl₂N₂O₂ 72.90 5.62  4.59 for Cl J=6, 14Hz, 1H), 3.12(m, 1H), 73.56 5.70  4.66 isotope), 3.60(dd, J=8, 14Hz, 1H), Exact 3.81(s, 3H), 3.90-4.16(m, 3H), M.S. 6.73-6.96(m, 4H), 6.96- Theory: 7.30(m, 12H), 7.30-7.49 609.2075, (m, 6H) Found: 609.2053 177 PhCH₂ MeCO foam 554 (M⁺) CDCl₃ 2:1 mixture of amide C₃₈H₃₈N₂O₂ 82.28 6.90  5.05 rotamers 1.90(s, 2/3•3H), 1.95 82.01 6.96  5.25 (s, 1/3•3H), 2.36-2.53 (m, 2H), 2.63(dd, J=4, 13Hz, 1H), 3.00(m, 1H), 3.06-3.23 (m, 2H), 3.66(s, 1/3•3H), 3.76(s, 2/3•3H), 3.85(ABq, J=17Hz, Δν=110Hz, 2/3•2H), 4.59(ABq, J=17Hz, Δν=100Hz, 1/3•2H), 6.42(d, J=7Hz, 1H), 6.68- 6.85(m, 3H), 6.92-7.05(m, 2H), 7.05-7.43(m, 12H), 7.50- 7.63(m, 6H)

The biological activity of the compounds of the present invention was evaluated employing an initial screening assay which rapidly and accurately measured the binding of the tested compound to known NK-1 and NK-2 receptor sites. Assays useful for evaluating tachykinin receptor antagonists are well known in the art. See. e.a., J. Jukic, et al., Life Sciences, 49:1463-1469 (1991); N. Kucharczyk, et al., Journal of Medicinal Chemistry, 36:1654-1661 (1993); N. Rouissi, et al., Biochemical and Biophysical Research Communications, 176:894-901 (1991).

NK-1 Receotor Bindina Assay

Radioreceptor binding assays were performed using a derivative of a previously published protocol. D. G. Payan, et al., Journal of Immunology, 133:3260-3265 (1984). In this assay an aliquot of IM9 cells (1×10⁶ cells/tube in RPMI 1604 medium supplemented with 10% fetal calf serum) was incubated with 20 pM ¹²⁵I-labeled substance P in the presence of increasing competitor concentrations for 45 minutes at 4° C.

The IM9 cell line is a well-characterized and readily available human cell line. See, e.g., Annals of the New York Academy of Science, 190: 221-234 (1972); Nature (London), 251:443-444 (1974); Proceedings of the National Academy of Sciences (USA), 71:84-88 (1974). These cells were routinely cultured in RPMI 1640 supplemented with 50 μg/ml gentamicin sulfate and 10% fetal calf serum.

The reaction was terminated by filtration through a glass fiber filter harvesting system using filters previously soaked for 20 minutes in 0.1% polyethylenimine. Specific binding of labeled substance P was determined in the presence of 20 nM unlabeled ligand.

NK-2 Receptor Binding Assay

The CHO-hNK-2R cells, a CHO-derived cell line transformed with the human NK-2 receptor, expressing about 400,000 such receptors per cell, were grown in 75 cm² flasks or roller bottles in minimal essential medium (alpha modification) with 10% fetal bovine serum. The gene sequence of the human NK-2 receptor is given in N. P. Gerard, et al., Journal of Bioloaical Chemistry, 265:20455-20462 (1990).

For preparation of membranes, 30 confluent roller bottle cultures were dissociated by washing each roller bottle with 10 ml of Dulbecco's phosphate buffered saline (PBS) without calcium and magnesium, followed by addition of 10 ml of enzyme-free cell dissociation solution (PBS-based, from Specialty Media, Inc.). After an additional 15 minutes, the dissociated cells were pooled and centrifuged at 1,000 RPM for 10 minutes in a clinical centrifuge. Membranes were prepared by homogenization of the cell pellets in 300 ml 50 mM Tris buffer, pH 7.4 with a Tekmar® homogenizer for 10-15 seconds, followed by centrifugation at 12,000 RPM (20,000×g) for 30 minutes using a Beckman JA-14® rotor. The pellets were washed once using the above procedure. and the final pellets were resuspended in 100-120 ml 50 mM Tris buffer, pH 7.4, and 4 ml aliquots stored frozen at −70° C. The protein concentration of this preparation was 2 mg/ml.

For the receptor binding assay, one 4-ml aliquot of the CHO-hNK-2R membrane preparation was suspended in 40 ml of assay buffer containing 50 mM Tris, pH 7.4, 3 mM manganese chloride, 0.02% bovine serum albumin (BSA) and 4 μg/ml chymostatin. A 200 μl volume of the homogenate (40 μg protein) was used per sample. The radioactive ligand was [¹²⁵I]iodohistidyl-neurokinin A (New England Nuclear, NEX-252), 2200 Ci/mmol. The ligand was prepared in assay buffer at 20 nCi per 100 μl; the final concentration in the assay was 20 pM. Non-specific binding was determined using 1 μM eledoisin. Ten concentrations of eledoisin from 0.1 to 1000 nM were used for a standard concentration-response curve.

All samples and standards were added to the incubation in 10 μl dimethylsulfoxide (DMSO) for screening (single dose) or in 5 μl DMSO for IC₅₀ determinations. The order of additions for incubation was 190 or 195 μl assay buffer, 200 μl homogenate, 10 or 5 μl sample in DMSO, 100 μl radioactive ligand. The samples were incubated 1 hr at room temperature and then filtered on a 48 well Brandel cell harvester through GF/B filters which had been presoaked for two hours in 50 mM Tris buffer, pH 7.7, containing 0.5% BSA. The filter was washed 3 times with approximately 3 ml of cold 50 mM Tris buffer, pH 7.7. The filter circles were then punched into 12×75 mm polystyrene tubes and counted in a gamma counter.

Table II, infra, depicts the results of several such neurokinin binding assays. Column 1 provides the example number of the test antagonist compound as detailed in Table 1, supra. The next colums define the the concentration of the test compound (in nanomolar quantities) which inhibits fifty percent of the binding of the appropriate neurokinin, as defined in the column heading, or the percent inhibition of such binding at the concentration noted. Certain values represent the average of more than one experiment.

TABLE II NK-1 NK-2 Example IC₅₀ IC₅₀ No. nM nM  1 53 1700  2 36  3 29  4 40 1500  5 62  6 62% @ 1 μM  7 230  8 130  9 84  640  10 19  820  11 65 2400  12 1.6 1600  13 1.3  14 3.1 1000  15 2.1  16 4.2 1200  17 0.85 1600  18 1.1  19 434  20 6.0  870  21 4.6 1200  22 2.1 3300  23 13  810  24 1.2  640  25 4.4  480  26 0.75  650  27 1.6  710  28 1.7 1000  29 1.5 1500  30 1.0  680  31 9.2 6200  32 0.98 1100  33 1.9  670  34 6.2  590  35 0.89  600  36 10  120  37 4.2  600  38 30% @ 5 μM 8000  39 139  40 21.3  910  41 7.7  930  42 16% @ 1 μM 1200  43 179  39  44 25 54% at 10 μM  45 65 5300  46 2.2 2400  47 0.25 1800  48 0.24  49 135  50 0.25 3400  51 0.37  52 250  53 58% @ 5 μM 5200  54 30.1 2100  55 71  56  57 150  58 14  340  59 7.3 3700  60 24 3900  61 7.2  940  62 43 5900  63 74  490  64 30  240  65 7.2  600  66 4.6 7200  67 3.8  750  68 0.41 2400  69 5.4  830  70 13 1000  71 7.5 8900  73 0.99  74 0.36 1000  75 0.18  850  76 69 1400  77 0.88  630  78 10 2100  79 38 6100  80 19 3400  81 13 1100  82 13 1200  83 8.4 5200  84 41.1  510  86 0.36  87 0.77  88 120 5600  89 170 1200  90 65  91 3000  92 97.2  93 16% @ 1 μM  94 85  760  95 9.6 1000  96 34.4  97 1300  98 21  600  99 15% @ 1 μM 54% @ 10 μM 100 77% @ 1 μM 40% @ 10 μM 101 97 6000 102 210 59% @ 10 μM 103 82 3700 104 0.62 1600 105 630 15200  106 68 33% @ 10 μM 107 74% @ 1 μM  420 108 76% @ 1 μM 3500 109 190 2000 110 148  120 111 1200  490 112 270 113 7.8 1200 114 29.2  940 115 15.4 116 58  930 117 33 118 310 119 9.5 2700 120 2500 121 850 122 550 123 27 2500 124 0.93 1400 125 0.66 2100 126 2.8 3400 127 7.3 3000 128 1.1 129 8.5 130 19 131 67  131a 0.7 132 4.2 133 11.6 134 14% @ 1 μM 135 75% @ 1 μM  430 136 47% @ 1 μM  710 137 220 2700 138 770 2500 139 396  580 140 3.1 3000 141 11  260 142 8.6  830 143 7.9 144 52 1200 145 76 1900 146 420 3900 147 196  430 148 24 8500 149 1.2 150 45% @ 1 μM 151 1400 1700 152 1200 2000 153 650  540 154 76% @ 1 μM  210 155 63% @ 5 μM 12200  156 78% @ 5 μM 9500 157 88% @ 5 μM 2900 158 450 3800 159 54% @ 5 μM    11 @ 10 μM 160  0% @ 5 μM 19000  161 24% @ 5 μM  0% @ 10 μM  161a 77% @ 5 μM 17600  162 375  0% @ 10 μM 163 44% @ 10 μM 164  0% @ 5 μM 6200 165  3% @ 5 μM 10450  166  0% @ 5 μM 10000  167  0% @ 5 μM 21000  168 13% @ 5 μM >100000    169  8% @ 5 μM 13900  170 67  2% @ 10 μM 171  0% @ 5 μM  6% @ 10 μM 172 46% @ 5 μM 173 74 2000 174  0% @ 5 μM 6400 175 28% @ 5 μM  9% @ 10 μM 176  9% @ 5 μM  0% @ 10 μM 177  0% @ 10 μM 12% @ 10 μM

Since the compounds of Formula I are effective tachykinin receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of tachykinin. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of tachykinins, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The term “physiological disorder associated with an excess of tachykinins” encompasses those disorders associated with an inappropriate stimulation of tachykinin receptors, regardless of the actual amount of tachykinin present in the locale.

These physiological disorders may include disorders of the central nervous system such as anxiety, depression, psychosis, and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer's type, Alzheimer's disease, AIDS-associated dementia, and Down's syndrome; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis and other neuropathological disorders such as peripheral neuropathy, such as diabetic and chemotherapy-induced neuropathy, and post-herpetic and other neuralgias; acute and chronic obstructive airway diseases such as adult respiratory distress syndrome, bronchopneumonia, bronchospasm, chronic bronchitis, drivercough, and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, and rheumatoid arthritis; disorders of the musculo-skeletal system, such as osteoporosis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatites; addiction disorders such as alcoholism; stress-related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal disorders or diseases associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; disorders of bladder function such as bladder detrusor hyper-reflexia and incontinence; artherosclerosis; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; irritative symptoms of benign prostatic hypertrophy; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine, and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example the compounds of Formula I may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis, and schizophrenia; neurodegenerative disorders such as Alzheimer's disease and Down's syndrome; respiratory diseases such as bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological disorders such as rejection of transplanted tissues; gastrointestinal disorders and diseases such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and irritable bowel syndrome; incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.

The results of several experiments demonstrate that many of the compounds of Formula I are selective tachykinin receptor antagonists. These compounds preferentially bind one tachykinin receptor subtype compared to other such receptors. Such compounds are especially preferred.

For example, NK-1 antagonists are most especially preferred in the treatment of pain, especially chronic pain, such as neuropathic pain, post-operative pain, and migraines, pain associated with arthritis, cancer-associated pain, chronic lower back pain, cluster headaches, herpes neuralgia, phantom limb pain, central pain, dental pain, neuropathic pain, opiod-resistant pain, visceral pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, post partum pain, angina pain, and genitourinary tract-related pain including cystitis.

In addition to pain, NK-1 antagonists are especially preferred in the treatment and prevention of urinary incontinence; irritative symptoms of benign prostatic hypertrophy; motility disorders of the gastrointestinal tract, such as irritable bowel syndrome; acute and chronic obstructive airway diseases, such as bronchospasm, bronchopneumonia, asthma, and adult respiratory distress syndrome; artherosclerosis; inflammatory conditions, such as inflammatory bowel disease, ulcerative colitis, Crohn's disease, rheumatoid arthritis, osteoarthritis, neurogenic inflammation, allergies, rhinitis, cough, dermatitis, urticaria, psoriasis, conjunctivitis, irritation-induced miosis; tissue transplant rejection; plasma extravasation resulting from cytokine chemotherapy and the like; spinal cord trauma; stroke; cerebral stroke (ischemia); Alzheimer's disease; Parkinson's disease; multiple sclerosis; amyotrophic lateral sclerosis; schizophrenia; anxiety; and depression.

NK-2 antagonists are especially preferred in the treatment of urinary incontinence, bronchospasm, asthma, adult respiratory distress syndrome, motility disorders of the gastrointestinal tract, such as irritable bowel syndrome, and pain.

In addition to the in vitro binding assays described suora, many of the compounds of this invention have also been tested in vivo model systems for conditions associated with an excess of tachykinins. Of these compounds tested in vivo many have shown efficacy against said conditions.

The compounds of Formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

The present invention also includes pharmaceutical compositions which contain, as the active ingredient, the compounds of Formula I associated with pharmaceutically acceptable carriers. In making the compositions of the present invention the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

The active compound is effective over a wide dosage range. For examples, dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred. However, it will be understood that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several smaller doses for administration throughout the day.

For preparing solid compositions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dipsersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compsoitions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

The following examples illustrate the pharmaceutical compositions of the present invention.

FORMULATION EXAMPLE 1

Hard gelatin capsules containing the following ingredients are prepared:

Quantity Ingredient (mg/capsule) Compound of Example 51 30.0 Starch 305.0 Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.

FORMULATION EXAMPLE 2

A tablet formula is prepared using the ingredients below:

Quantity Ingredient (mg/tablet) Compound of Example 66 25.0 Cellulose, microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets, each weighing 240 mg.

FORMULATION EXAMPLE 3

A dry powder inhaler formulation is prepared containing the following components:

Ingredient Weight % Compound of Example 17  5 Lactose 95

The active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.

FORMULATION EXAMPLE 4

Tablets, each containing 30 mg of active ingredient, are prepared as follows:

Quantity Ingredient (mg/tablet) Compound of Example 14 30.0 mg Starch 45.0 mg Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10% solution in water) Sodium carboxymethyl starch 4.5 mg Magnesium stearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50-60° C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.

FORMULATION EXAMPLE 5

Capsules, each containing 40 mg of medicament are made as follows:

Quantity Ingredient (mg/capsule) Compound of Example 13 40.0 mg Starch 109.0 mg Magnesium stearate 1.0 mg Total 150.0 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.

FORMULATION EXAMPLE 6

Suppositories, each containing 25 mg of active ingredient are made as follows:

Ingredient Amount Compound of Example 18 25 mg Saturated fatty acid glycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.

FORMULATION EXAMPLE 7

Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:

Ingredient Amount Compound of Example 43 50.0 mg Xanthan gum 4.0 mg Sodium carboxymethyl cellulose (11%) 50.0 mg Microcrystalline cellulose (89%) Sucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purified water to 5.0 ml

The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

FORMULATION EXAMPLE 8

Capsules, each containing 15 mg of medicament, are made as follows:

Quantity Ingredient (mg/capsule) Compound of Example 58 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total 425.0 mg

The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.

FORMULATION EXAMPLE 9

An intravenous formulation may be prepared as follows:

Ingredient Quantity Compound of Example 91 250.0 mg Isotonic saline 1000 ml

FORMULATION EXAMPLE 10

A topical formulation may be prepared as follows:

Ingredient Quantity Compound of Example 67 1-10 g Emulsifying Wax 30 g Liquid Paraffin 20 g White Soft Paraffin to 100 g

The white soft paraffin is heated until molten. The liquid praffin and emulsifying wax are incorporated and stirred until dissolved. The compound of Example 67 is added and stirring is continued until dispersed. The mixture is then cooled until solid.

Another preferred formulation employed in the methods of the present invention is the use of transdermal patches. Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. Such patches may be constructed for continous, pulsatile, or on demand delivery of pharmaceutical agents.

4 5 amino acids amino acid linear peptide 1 Phe Xaa Gly Leu Met 1 5 11 amino acids amino acid linear peptide 2 Arg Pro Lys Pro Gln Gln Phe Phe Gly Leu Met 1 5 10 10 amino acids amino acid linear peptide 3 His Lys Thr Asp Ser Phe Val Gly Leu Met 1 5 10 10 amino acids amino acid linear peptide 4 Asp Met His Asp Phe Phe Val Gly Leu Met 1 5 10 

We claim:
 1. A compound of the formula

wherein: R¹ is hexamethyleneiminyl; which may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, piperidinyl, pyrimidinyl, C₂-C₆ alkanoylamino, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl; any one of which phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, C₁-C₄ alkyl, piperidinyl, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl groups may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino; R² is —CO—R⁶; R⁶ is hydrogen, C₁-C₄ alkyl, C₁-C₃ haloalkyl, phenyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, amino, C₁-C₄ alkylamino, or di(C₁-C₄ alkyl)amino R^(a) is halo, C₁-C₃ alkoxy, C₁-C₃ alkylthio, nitro, trifluoromethyl, or C₁-C₃ alkyl; and R^(b) is hydrogen, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C_(4 alkylamino, or di(C) ₁-C₄ alkyl)amino; or pharmaceutically acceptable salt or solvate thereof.
 2. A compound as claimed in claim 1 wherein R^(b) is hydrogen or C₁-C₄ alkyl.
 3. A compound as claimed in claim 2 wherein R^(a) is C₁-C₃ alkoxy, chloro, fluoro, trifluoromethyl, or C₁-C₃ alkylthio.
 4. A method for the treatment of a physiological disorder associated with an excess of tachykinins, selected from the group consisting of fibrositis, osteoarthritis, rheumatoid asthma, arthritis, pain and nociception, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of the formula

wherein: R¹ is hexamethyleneiminyl; which may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, piperidinyl, pyrimidinyl, C₂-C₆ alkanoylamino, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl; any one of which phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, C₁-C₄ alkyl, piperidinyl, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl groups may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino; R² is —CO—R⁶; R⁶ is hydrogen, C₁-C₄ alkyl, C₁-C₃ haloalkyl, phenyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, amino, C₁-C₄ alkylarnino, or di(C₁-C₄ alkyl)amino R^(a) is halo, C₁-C₃ alkoxy, C₁-C₃ alkylthio, nitro, trifluoromethyl, or C₁-C₃ alkyl; and R^(b) is hydrogen, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, or di(C₁-C₄ alkyl)amino; or pharmaceutically acceptable salt or solvate thereof.
 5. A method as claimed in claim 4 employing a compound wherein R^(b) is hydrogen or C₁-C₄ alkyl.
 6. A method as claimed in claim 5 employing a compound wherein R^(a) is C₁-C₃ alkoxy, chloro, fluoro, trifluoromethyl, or C₁-C₃ alkylthio.
 7. A pharmaceutical formulation comprising an effective amount of a compound of the formula

wherein: R¹ is hexamethyleneiminyl; which may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, piperidinyl, pyrimidinyl, C₂-C₆ alkanoylamino, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl; any one of which phenyl, piperazinyl, C₃-C₈ cycloalkyl, benzyl, C₁-C₄ alkyl, piperidinyl, pyrrolidinyl, C₂-C₆ alkanoyl, or C₁-C₄ alkoxycarbonyl groups may be substituted with halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, di(C₁-C₄ alkyl)amino, or C₂-C₄ alkanoylamino; R² is —CO—R⁶; R⁶ is hydrogen, C₁-C₄ alkyl, C₁-C₃ haloalkyl, phenyl, C₁-C₃ alkoxy, C₁-C₃ hydroxyalkyl, amino, C₁-C₄ alkylamino, or di(C₁-C₄ alkyl)amino R^(a) is halo, C₁-C₃ alkoxy, C₁-C₃ alkylthio, nitro, trifluoromethyl, or C₁-C₃ alkyl; and R^(b) is hydrogen, halo, C₁-C₄ alkyl, C₁-C₄ alkoxy, trifluoromethyl, amino, C₁-C₄ alkylamino, or di(C₁-C₄ alkyl)amino; or pharmaceutically acceptable salt or solvate thereof, in combination with a suitable pharmaceutical excipient, diluent, or carrier.
 8. A formulation as claimed in claim 7 employing a compound wherein R^(b) is hydrogen or C₁-C₆ alkyl.
 9. A formulation as claimed in claim 7 employing a compound wherein R^(a) is C₁-C₃ alkoxy, chloro, fluoro, trifluoromethyl, or C₁-C₃ alkylthio. 